Pyridazinone derivatives

ABSTRACT

Compounds of the formula (I), in which R 1 , R 2 , R 3 , R 4 , R 4′  have the meanings indicated in claim 1, are inhibitors of tyrosine kinases, in particular Met kinase, and can be employed, inter alia, for the treatment of tumors.

BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

The present invention relates to compounds and to the use of compoundsin which the inhibition, regulation and/or modulation of signaltransduction by kinases, in particular tyrosine kinases and/orserine/threonine kinases, plays a role, furthermore to pharmaceuticalcompositions which comprise these compounds, and to the use of thecompounds for the treatment of kinase-induced diseases.

In particular, the present invention relates to compounds and to the useof compounds in which the inhibition, regulation and/or modulation ofsignal transduction by Met kinase plays a role.

One of the principal mechanisms by which cellular regulation is effectedis through the transduction of extracellular signals across the membranethat in turn modulate biochemical pathways within the cell. Proteinphosphorylation represents one course by which intracellular signals arepropagated from molecule to molecule resulting finally in a cellularresponse. These signal transduction cascades are highly regulated andoften overlap, as is evident from the existence of many protein kinasesas well as phosphatases. Phosphorylation of proteins occurspredominantly at serine, threonine or tyrosine residues, and proteinkinases have therefore been classified by their specificity ofphosphorylation site, i.e. serine/threonine kinases and tyrosinekinases. Since phosphorylation is such a ubiquitous process within cellsand since cellular phenotypes are largely influenced by the activity ofthese pathways, it is currently believed that a number of disease statesand/or diseases are attributable to either aberrant activation orfunctional mutations in the molecular components of kinase cascades.Consequently, considerable attention has been devoted to thecharacterisation of these proteins and compounds that are able tomodulate their activity (for a review see: Weinstein-Oppenheimer et al.Pharma. &. Therap., 2000, 88, 229-279).

The role of the receptor tyrosine kinase Met in human oncogenesis andthe possibility of inhibition of HGF (hepatocyte growth factor)dependentMet activation are described by S. Berthou et al. in Oncogene, Vol. 23,No. 31, pages 5387-5393 (2004). The inhibitor SU11274 described therein,a pyrrole-indoline compound, is potentially suitable for combatingcancer. Another Met kinase inhibitor for cancer therapy is described byJ. G. Christensen et al. in Cancer Res. 2003, 63(21), 7345-55.

A further tyrosine kinase inhibitor for combating cancer is reported byH. Hov et al. in Clinical Cancer Research Vol. 10, 6686-6694 (2004). Thecompound PHA-665752, an indole derivative, is directed against the HGFreceptor c-Met. It is furthermore reported therein that HGF and Met makea considerable contribution to the malignant process of various forms ofcancer, such as, for example, multiple myeloma.

The synthesis of small compounds which specifically inhibit, regulateand/or modulate signal transduction by tyrosine kinases and/orserine/|threonine kinases, in particular Met kinase, is thereforedesirable and an aim of the present invention.

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

The present invention specifically relates to compounds of the formula Iwhich inhibit, regulate and/or modulate signal transduction by Metkinase, to compositions which comprise these compounds, and to processesfor the use thereof for the treatment of Met kinase-induced diseases andcomplaints, such as angiogenesis, cancer, tumour formation, growth andpropagation, arteriosclerosis, ocular diseases, such as age-inducedmacular degeneration, choroidal neovascularisation and diabeticretinopathy, inflammatory diseases, arthritis, thrombosis, fibrosis,glomerulonephritis, neurodegeneration, psoriasis, restenosis, woundhealing, transplant rejection, metabolic diseases and diseases of theimmune system, also autoimmune diseases, cirrhosis, diabetes anddiseases of the blood vessels, also instability and permeability and thelike in mammals.

Solid tumours, in particular fast-growing tumours, can be treated withMet kinase inhibitors. These solid tumours include monocytic leukaemia,brain, urogenital, lymphatic system, stomach, laryngeal and lungcarcinoma, including lung adenocarcinoma and small-cell lung carcinoma.

The present invention is directed to processes for the regulation,modulation or inhibition of Met kinase for the prevention and/ortreatment of diseases in connection with unregulated or disturbed Metkinase activity. In particular, the compounds of the formula I can alsobe employed in the treatment of certain forms of cancer. The compoundsof the formula I can furthermore be used to provide additive orsynergistic effects in certain existing cancer chemotherapies, and/orcan be used to restore the efficacy of certain existing cancerchemotherapies and radiotherapies.

The compounds of the formula I can furthermore be used for the isolationand investigation of the activity or expression of Met kinase. Inaddition, they are particularly suitable for use in diagnostic methodsfor diseases in connection with unregulated or disturbed Met kinaseactivity.

It can be shown that the compounds according to the invention have anantiproliferative action in vivo in a xenotransplant tumour model. Thecompounds according to the invention are administered to a patienthaving a hyperproliferative disease, for example to inhibit tumourgrowth, to reduce inflammation associated with a lymphoproliferativedisease, to inhibit transplant rejection or neurological damage due totissue repair, etc. The present compounds are suitable for prophylacticor therapeutic purposes. As used herein, the term “treatment” is used torefer to both prevention of diseases and treatment of pre-existingconditions. The prevention of proliferation is achieved byadministration of the compounds according to the invention prior to thedevelopment of overt disease, for example to prevent the growth oftumours, prevent metastatic growth, diminish restenosis associated withcardiovascular surgery, etc. Alternatively, the compounds are used forthe treatment of ongoing diseases by stabilising or improving theclinical symptoms of the patient.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to induce cell death or to inhibitmigration, usually between about one hour and one week. In vitro testingcan be carried out using cultivated cells from a biopsy sample. Theviable cells remaining after the treatment are then counted.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93)and models of transgenic animals (for example White et al., Oncogene,2001, 20, 7064-7072). For the determination of certain stages in thesignal transduction cascade, interacting compounds can be utilised inorder to modulate the signal (for example Stephens et al., BiochemicalJ., 2000, 351, 95-105). The compounds according to the invention canalso be used as reagents for testing kinase-dependent signaltransduction pathways in animals and/or cell culture models or in theclinical diseases mentioned in this application.

Measurement of the kinase activity is a technique which is well known tothe person skilled in the art. Generic test systems for thedetermination of the kinase activity using substrates, for examplehistone (for example Alessi et al., FEBS Lett. 1996, 399, 3, pages333-338) or the basic myelin protein, are described in the literature(for example Campos-González, R. and Glenney, Jr., J. R. 1992, J. Biol.Chem. 267, page 14535).

For the identification of kinase inhibitors, various assay systems areavailable. In scintillation proximity assay (Sorg et al., J. of.Biomolecular Screening, 2002, 7, 11-19) and flashplate assay, theradioactive phosphorylation of a protein or peptide as substrate withγATP is measured. In the presence of an inhibitory compound, a decreasedradioactive signal, or none at all, is detectable. Furthermore,homogeneous time-resolved fluorescence resonance energy transfer(HTR-FRET) and fluorescence polarisation (FP) technologies are suitableas assay methods (Sills et al., J. of Biomolecular Screening, 2002,191-214).

Other non-radioactive ELISA assay methods use specificphospho-antibodies (phospho-ABs). The phospho-AB binds only thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated anti-sheepantibody (Ross et al., 2002, Biochem. J.).

There are many diseases associated with deregulation of cellularproliferation and cell death (apoptosis). The conditions of interestinclude, but are not limited to, the following. The compounds accordingto the invention are suitable for the treatment of various conditionswhere there is proliferation and/or migration of smooth muscle cellsand/or inflammatory cells into the intimal layer of a vessel, resultingin restricted blood flow through that vessel, for example in the case ofneointimal occlusive lesions. Occlusive graft vascular diseases ofinterest include atherosclerosis, coronary vascular disease aftergrafting, vein graft stenosis, peri-anastomatic prosthetic restenosis,restenosis after angioplasty or stent placement, and the like.

PRIOR ART

-   Other pyridazine derivatives are described as MET kinase inhibitors    in WO 2007/065518.-   Thiadiazinones are described in DE19604388, WO2003/037349    WO2007/057093 or WO2007/057092.-   Dihydropyridazinones for combating cancer are described in WO    03/037349 A1.-   Other pyridazines for the treatment of diseases of the immune    system, ischaemic and inflammatory diseases are known from EP 1 043    317 A1 and EP 1 061 077 A1.-   EP 0 738 716 A2 and EP 0 711 759 B1 describe other    dihydropyridazinones and pyridazinones as fungicides and    insecticides.-   Other pyridazinones are described as cardiotonic agents in U.S. Pat.    No. 4,397,854. JP 57-95964 discloses other pyridazinones.

The use of other MET kinase inhibitors for combating cancer is describedin WO 2007/075567.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   R¹ denotes Ar or Het,-   R² denotes an unsaturated, saturated or aromatic 6-membered    heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted by Hal, A,    [C(R³)₂]_(n)OR³, N═CR³N(R³)₂, SR³, NO₂, CN, COOR³, CON(R³)₂, NR³COA,    NR³SO₂A, SO₂N(R³)₂, S(O)_(m)A, [C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)Het,    O[C(R³)₂]_(p)OR³, O[C(R³)₂]_(n)N(R³)₂,    O[C(R³)₂]_(n)C≡C[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)N^(+O) ⁻(R³)₂,    O[C(R³)₂]_(n)Het, S[C(R³)₂]_(n)N(R³)₂, S[C(R³)₂]_(n)Het,    NR³[C(R³)₂]_(n)N(R³)₂, NR³[C(R³)₂]_(n)Het, NHCON(R³)₂,    NHCONH[C(R³)₂]_(n)N(R³)₂, NHCONH[C(R³)₂]_(n)Het,    NHCO[C(R³)₂]_(n)N(R³)₂, NHCO[C(R³)₂]_(n)Het, CON(R³)₂,    CONR³[C(R³)₂]_(n)N(R³)₂, CONR³[C(R³)₂]_(n)NR³COOA,    CONR³[C(R³)₂]_(n)OR³, CONR³[C(R³)₂]_(n)Het, COHet, COA, CH═CH—COOR³,    CH═CH—N(R³)₂ and/or ═O (carbonyl oxygen),-   R³ denotes H or A,-   R⁴, R^(4′) each, independently of one another, denote H, Hal, A,    OR³, CN, COOR³, CON(R³)₂, NR³COA, NR³SO₂A, SO₂N(R³)₂ or S(O)_(m)A,-   Ar denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di- or trisubstituted by Hal, A,    [C(R³)₂]_(n)OR³, [C(R³)₂]_(n)N(R³)₂, SR³, NO₂, CN, COOR³, CON(R³)₂,    NR³COA, NR³SO₂A, SO₂N(R³)₂, S(O)_(m)A, CO-Het, Het,    O[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)Het, NHCOOA, NHCON(R³)₂,    NHCOO[C(R³)₂]_(n)N(R³)₂, NHCOO[C(R³)₂]_(n)-Het,    NHCONH[C(R³)₂]_(n)N(R³)₂, NHCONH[C(R³)₂]_(n)Het,    OCONH[C(R³)₂]_(n)N(R³)₂, OCONH[C(R³)₂]_(n)Het,    CONR³[C(R³)₂]_(n)N(R³)₂, CONR³[C(R³)₂]_(n)Het and/or COA,-   Het denotes a mono-, bi- or tricyclic saturated, unsaturated or    aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by    Hal, A, [C(R³)₂]_(n)OR³, [C(R³)₂]_(n)N(R³)₂, SR³, NO₂, CN, COOR³,    CON(R³)₂, NR³COA, NR³SO₂A, SO₂N(R³)₂, S(O)_(m)A, CO-Het¹,    [C(R³)₂]_(n)Het¹, O[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)Het¹, NHCOOA,    NHCON(R³)₂, NHCOO[C(R³)₂]_(n)N(R³)₂, NHCOO[C(R³)₂]_(n)Het¹,    NHCONH[C(R³)₂]_(n)N(R³)₂, NHCONH[C(R³)₂]_(n)Het¹,    OCONH[C(R³)₂]_(n)N(R³)₂, OCONH[C(R³)₂]_(n)Het¹, CO-Het¹, CHO, COA,    ═S, ═NH, ═NA and/or ═O (carbonyl oxygen), and where a ring nitrogen    may be oxidised,-   Het¹ denotes a monocyclic saturated heterocycle having 1 to 2 N    and/or O atoms, which may be mono- or disubstituted by A, OA, OH,    Hal and/or ═O (carbonyl oxygen),-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    1-7 H atoms may be replaced by F and/or in which one or two    non-adjacent CH₂ groups may be replaced by O, NH, S, SO, SO₂ and/or    by CH═CH groups,    -   or    -   cyclic alkyl having 3-7 C atoms,-   Hal denotes F, Cl, Br or I,-   m denotes 0, 1 or 2,-   n denotes 0, 1, 2, 3 or 4,-   p denotes 1, 2, 3 or 4,    and pharmaceutically usable derivatives, solvates, salts, tautomers    and stereoisomers thereof, including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term solvates of thecompounds is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force solvatesare, for example, mono- or dihydrates or alkoxides.

The term pharmaceutically usable derivatives is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds.

The term prodrug derivatives is taken to mean compounds of the formula Iwhich have been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the effective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to Claims 1-10 and pharmaceutically usable derivatives,salts, solvates, tautomers and stereoisomers thereof, characterised inthat

-   a) a compound of the formula II

in which R¹ has the meaning indicated in Claim 1,

-   is reacted with a compound of the formula III

in which R², R³, R⁴ and R^(4′) have the meanings indicated in Claim 1and L denotes Cl, Br, I or a free or reactively functionally modified OHgroup,or

-   b) a radical R² is converted into another radical R² by-   i) converting an oxadiazole radical into a pyrimidinyl radical,-   ii) acylating or alkylating an amino group,-   iii) etherifying a hydroxyl group,    or-   c) that it is liberated from one of its functional derivatives by    treatment with a solvolysing or hydrogenolysing agent,    and/or    a base or acid of the formula I is converted into one of its salts.

Above and below, the radicals R¹, R², R³, R⁴, R^(4′) have the meaningsindicated for the formula I, unless expressly stated otherwise.

A denotes alkyl, this is unbranched (linear) or branched, and has 1, 2,3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl,furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl.

Cyclic alkyl(cycloalkyl) preferably denotes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

Ar denotes, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-,m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- orp-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl,o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- orp-(N-methylaminocarbonyl)phenyl, o-, m- or p-acetamidophenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- orp-ethoxycarbonylphenyl, o-, m- or p-(N,N-di-methylamino)phenyl, o-, m-or p-(N,N-dimethylaminocarbonyl)phenyl, o-, m- orp-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)phenyl, o-, m- orp-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-,m- or p-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl,o-, m- or p-methylsulfanylphenyl, o-, m- or p-cyanophenyl, o-, m- orp-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- orp-formylphenyl, o-, m- or p-acetylphenyl, o-, m- orp-aminosulfonylphenyl, o-, m- or p-(morpholin-4-ylcarbonyl)phenyl, o-,m- or p-(morpholin-4-ylcarbonyl)phenyl, o-, m- orp-(3-oxomorpholin-4-yl)phenyl, o-, m- or p-(piperidinylcarbonyl)phenyl,o-, m- or p-[2-(morpholin-4-yl)ethoxy]phenyl, o-, m- orp-[3-(N,N-diethylamino)propoxy]phenyl, o-, m- orp-[3-(3-diethylaminopropyl)ureido]phenyl, o-, m- orp-(3-diethylaminopropoxycarbonylamino)phenyl, furthermore preferably2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar furthermore preferably denotes phenyl, naphthyl or biphenyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by A, Hal, CN,S(O)_(m)A, NR³COA, CON(R³)₂, O[C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)OR³,CONR³[C(R³)₂]_(n)N(R³)₂ and/or CONR³[C(R³)₂]_(n)Het.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-,6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-,6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6-or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-,3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl,2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-,6-, 7- or 8-2H-benzo-1,4-oxazinyl, further preferably1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4-,-5-yl or 2,1,3-benzoxadiazol-5-yl, azabicyclo-[3.2.1]octyl ordibenzofuranyl.

The heterocyclic radicals may also be partially or fully hydrogenated.

-   Irrespective of further substitutions, Het can thus also denote, for    example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-,    -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl,    tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or    -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or    3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-,    -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl,    1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-,    -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or    4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl,    1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl,    hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl,    1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl,    1,2,3,4-tetrahydro-1-,-2-,-3-, -4-, -5-, -6-, -7- or -8-isoquinolyl,    2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl,    furthermore preferably 2,3-methylenedioxyphenyl,    3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl,    3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl,    2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxy)phenyl or    also 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore    preferably 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,    3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,    2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,    1,3-dihydroindole, 2-oxo-1,3-dihydroindole or    2-oxo-2,3-dihydrobenzimidazolyl.

Het preferably denotes piperidinyl, piperazinyl, pyrrolidinyl,morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl,tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl,benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl,azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, imidazolidinyl, azepanylor benzo-2,1,3-thiadiazolyl, each of which is unsubstituted or mono-,di-, tri-, tetra- or pentasubstituted by A, CHO, COOR³, CON(R³)₂,[C(R³)₂]_(n)Het¹, [C(R³)₂]_(n)OR³, [C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)Het¹and/or ═O (carbonyl oxygen),

and where a ring nitrogen may be oxidised.

Het¹ preferably denotes pyrrolidine, piperidine, piperazine ormorpholine, each of which is unsubstituted or mono- or disubstituted byA and/or ═O (carbonyl oxygen).

R¹ preferably denotes Ar or benzo-2,1,3-thiadiazolyl.

The unsaturated, saturated or aromatic 6-membered heterocycle having 1to 4 N and/or O atoms in the meaning for R² has, for example, thefollowing meanings: pyrimidine, pyridazine, pyridine, 1,3-oxazinane,morpholine, piperidine, piperazine, 1,4-dihydropyridine,1,2,3,4-tetrahydro-6-pyridine, tetrahydropyran, 1,4-dioxane,1,3-dioxane, hexahydropyridazine or hexahydropyrimidine.

R² preferably denotes pyrimidinyl, pyridazinyl, pyridinyl,1,3-oxazinanyl, morpholinyl, piperidinyl or piperazinyl, each of whichis unsubstituted or mono-, di- or trisubstituted by Hal, A,[C(R³)₂]_(n)OR³, N═CR³N(R³)₂, CN, COOR³, [C(R³)₂]_(n)N(R³)₂,[C(R³)₂]_(n)Het, O[C(R³)₂]_(p)OR³, O[C(R³)₂]_(n)N(R³)₂,O[C(R³)₂]_(n)C≡C[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)N⁺O⁻(R³)₂,O[C(R³)₂]_(n)Het, NR³[C(R³)₂]_(n)N(R³)₂, NR³[C(R³)₂]_(n)Het,[C(R³)₂]_(n)NHCO[C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)NHCO[C(R³)₂]_(n)Het,CONR³[C(R³)₂]_(n)N(R³)₂, CONR³[C(R³)₂]_(n)NR³COOA, CONR³[C(R³)₂]_(n)OR³,CONR³[C(R³)₂]_(n)Het, COHet, CH═CH—COOR³, CH═CH—N(R³)₂ and/or ═O(carbonyl oxygen).

-   R³ preferably denotes H, methyl, ethyl or propyl.-   R⁴, R^(4′) preferably denote H.

Hal preferably denotes F, Cl or Br, but also I, particularly preferablyF or Cl.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae la to II, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R² denotes an unsaturated, saturated or aromatic 6-membered    heterocycle having 1 to 4 N and/or O atoms, which may be    unsubstituted or mono-, di- or trisubstituted by Hal, A,    [C(R³)₂]_(n)OR³, N═CR³N(R³)₂, CN, COOR³, [C(R³)₂]_(n)N(R³)₂,    [C(R³)₂]_(n)Het, O[C(R³)₂]_(p)OR³, O[C(R³)₂]_(n)N(R³)₂,    O[C(R³)₂]_(n)C≡C[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)N⁺O⁻(R³)₂,    O[C(R³)₂]_(n)Het, NR³[C(R³)₂]_(n)N(R³)₂, NR³[C(R³)₂]_(n)Het,    [C(R³)₂]_(n)NHCO[C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)NHCO[C(R³)₂]_(n)Het,    CONR³[C(R³)₂]_(n)N(R³)₂, CONR³[C(R³)₂]_(n)NR³COOA,    CONR³[C(R³)₂]_(n)OR³, CONR³[C(R³)₂]_(n)Het, COHet, CH═CH—COOR³,    CH═CH—N(R³)₂ and/or ═O (carbonyl oxygen);-   in Ib Ar denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di- or trisubstituted by A, Hal, CN,    S(O)_(m)A, NR³COA, CON(R³)₂, O[C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)OR³,    CONR³[C(R³)₂]_(n)N(R³)₂ and/or CONR³[C(R3)₂]_(n)Het;-   in Ic R⁴, R^(4′) denote H;-   in Id Het denotes a mono-, bi- or tricyclic saturated, unsaturated    or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may    be unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by    A, CHO, COOR³, CON(R³)₂, [C(R³)₂]_(n)Het¹, [C(R³)₂]_(n)OR³,    [C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)Het¹ and/or ═O (carbonyl oxygen),    -   and where a ring nitrogen may be oxidised;-   in Ie Het¹ denotes a monocyclic saturated heterocycle having 1 to 2    N and/or O atoms, which may be mono- or disubstituted by A and/or ═O    (carbonyl oxygen);-   in If A denotes unbranched or branched alkyl having 1-8 C atoms, in    which 1-7 H atoms may be replaced by F and/or Cl;-   in Ig R¹ denotes Ar or benzo-2,1,3-thiadiazolyl;-   in Ih R³ denotes H, methyl, ethyl or propyl;-   in Ii R² denotes pyrimidinyl, pyridazinyl, pyridinyl,    1,3-oxazinanyl, morpholinyl, piperidinyl or piperazinyl, each of    which is unsubstituted or mono-, di- or trisubstituted by Hal, A,    [C(R³)₂]_(n)OR³, N═CR³N(R³)₂, CN, COOR³, [C(R³)₂]_(n)N(R³)₂,    [C(R³)₂]_(n)Het, O[C(R³)₂]_(p)OR³, O[C(R³)₂]_(n)N(R³)₂,    O[C(R³)₂]_(n)C≡C[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)N⁺ ⁻(R³)₂,    O[C(R³)₂]_(n)Het, NR³[C(R³)₂]_(n)N(R³)₂, NR³[C(R³)_(2]) _(n)Het,    [C(R³)₂]_(n)NHCO[C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)NHCO[C(R³)₂]_(n)Het,    CONR³[C(R³)₂]_(n)N(R³)₂, CONR³[C(R³)₂]_(n)NR³COOA,    CONR³[C(R³)₂]_(n)OR³, CONR³[C(R³)₂]_(n)Het, COHet, CH═CH—COOR³,    CH═CH—N(R³)₂ and/or ═O (carbonyl oxygen);-   in Ij Het denotes piperidinyl, piperazinyl, pyrrolidinyl,    morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,    oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl,    triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl,    pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,    benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl,    azabicyclo[2.2.2]octyl, imidazolidinyl, azepanyl or    benzo-2,1,3-thiadiazolyl, each of which is unsubstituted or mono-,    di-, tri-, tetra- or pentasubstituted by A, CHO, COOR³, CON(R³)₂,    [C(R³)₂]_(n)Het¹, [C(R³)₂]_(n)OR³, [C(R³)₂]_(n)N(R³)₂,    O[C(R³)₂]_(n)Het¹ and/or ═O (carbonyl oxygen),    -   and where a ring nitrogen may be oxidised;-   in Ik Het¹ denotes pyrrolidine, piperidine, piperazine or    morpholine, each of which is unsubstituted or mono- or disubstituted    by A and/or ═O (carbonyl oxygen);-   in Il R¹ denotes Ar or Het,    -   R² denotes pyrimidinyl, pyridazinyl, pyridinyl, 1,3-oxazinanyl,        morpholinyl, piperidinyl or piperazinyl, each of which is        unsubstituted or mono-, di- or trisubstituted by Hal, A,        [C(R³)₂]_(n)OR³, N═CR³N(R³)₂, CN, COOR³, [C(R³)₂]_(n)N(R³)₂,        [C(R³)₂]_(n)Het, O[C(R³)₂]_(p)OR³, O[C(R³)₂]_(n)N(R³)₂,        O[C(R³)₂]_(n)C≡C[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)N⁺O⁻(R³)₂,        O[C(R³)₂]_(n)Het, NR³[C(R³)₂]_(n)N(R³)₂, NR³[C(R³)₂]_(n)Het,        [C(R³)₂]_(n)NHCO[C(R³)₂]_(n)N(R³)₂,        [C(R³)₂]_(n)NHCO[C(R³)₂]_(n)Het, CONR³[C(R³)₂]_(n)N(R³)₂,        CONR³[C(R³)₂]_(n)NR³COOA, CONR³[C(R³)₂]_(n)OR³,        CONR³[C(R³)₂]_(n)Het, COHet, CH═CH—COOR³, CH═CH—N(R³)₂ and/or ═O        (carbonyl oxygen),    -   R³ denotes H, methyl, ethyl or propyl,    -   R⁴, R^(4′) denote H,    -   Ar denotes phenyl, naphthyl or biphenyl, each of which is        unsubstituted or mono-, di- or trisubstituted by A, Hal, CN,        S(O)_(m)A, NR³COA, CON(R³)₂, O[C(R³)₂]_(n)N(R³)₂,        [C(R³)₂]_(n)OR³, CONR³[C(R³)₂]_(n)N(R³)₂ and/or        CONR³[C(R³)₂]_(n)Het,    -   Het denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,        furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,        isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl,        triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl,        pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,        benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl,        azabicyclo[2.2.2]octyl, imidazolidinyl, azepanyl or        benzo-2,1,3-thiadiazolyl, each of which is unsubstituted or        mono-, di-, tri-, tetra- or pentasubstituted by A, CHO, COOR³,        CON(R³)₂, [C(R³)₂]_(n)Het¹, [C(R³)₂]_(n)OR³, [C(R³)₂]_(n)N(R³)₂,        O[C(R³)₂]_(n)Het¹ and/or ═O (carbonyl oxygen),        -   and where a ring nitrogen may be oxidised,    -   Het¹ denotes pyrrolidine, piperidine, piperazine or morpholine,        each of which is unsubstituted or mono- or disubstituted by A        and/or ═O (carbonyl oxygen),    -   A denotes unbranched or branched alkyl having 1-8 C atoms, in        which 1-7 H atoms may be replaced by F and/or Cl,    -   Hal denotes F, Cl, Br or I,    -   m denotes 0, 1 or 2,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 1, 2, 3 or 4;        and pharmaceutically usable derivatives, salts, solvates,        tautomers and stereoisomers thereof, including mixtures thereof        in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

The starting compounds of the formulae II and III are generally known.If they are novel, however, they can be prepared by methods known perse. The pyridazinones of the formula II used are, if not commerciallyavailable, generally prepared by the method of W. J. Coates, A.McKillop, Synthesis, 1993, 334-342.

Compounds of the formula I can preferably be obtained by reacting acompound of the formula II with a compound of the formula III. In thecompounds of the formula III, L preferably denotes Cl, Br, I or a freeor reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferablymethylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).

The reaction is generally carried out in the presence of an acid-bindingagent, preferably an organic base, such as DIPEA, triethylamine,dimethylaniline, pyridine or quinoline.

The addition of an alkali or alkaline earth metal hydroxide, carbonateor bicarbonate or another salt of a weak acid of the alkali or alkalineearth metals, preferably of potassium, sodium, calcium or caesium, mayalso be favourable.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 90°, in particular between about 0° andabout 70°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to acetonitrile, dichloromethane and/orDMF.

The reaction of a compound of the formula II with a compound of theformula III in which L denotes OH, is preferably carried out in aMitsunobu reaction by addition of, for example, triphenylphosphine and adialkyl azodicarboxylate. THF is preferred as solvent.

It is furthermore possible to convert a compound of the formula I intoanother compound of the formula I, for example by reducing nitro groupsto amino groups (for example by hydrogenation on Raney nickel orPd/carbon in an inert solvent, such as methanol or ethanol).

Free amino groups can furthermore be acylated in a conventional mannerusing an acid chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide, advantageously in an inert solvent, such asdichloromethane or THF, and/or in the presence of a base, such astriethylamine or pyridine, at temperatures between −60 and +30°.

The compounds of the formula I can furthermore be obtained by liberatingthem from their functional derivatives by solvolysis, in particularhydrolysis, or by hydrogenolysis.

Preferred starting materials for the solvolysis or hydrogenolysis arethose which contain corresponding protected amino and/or hydroxyl groupsinstead of one or more free amino and/or hydroxyl groups, preferablythose which carry an aminoprotecting group instead of an H atom bondedto an N atom, for example those which conform to the formula I, butcontain an NHR′ group (in which R′ is an aminoprotecting group, forexample BOC or CBZ) instead of an NH₂ group.

Preference is furthermore given to starting materials which carry ahydroxyl-protecting group instead of the H atom of a hydroxyl group, forexample those which conform to the formula I, but contain an R″O-phenylgroup (in which R″ is a hydroxylprotecting group) instead of ahydroxyphenyl group.

It is also possible for a plurality of—identical or different—protectedamino and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, they can in many cases be cleaved off selectively.

The term “aminoprotecting group” is known in general terms and relatesto groups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but are easy to remove after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are, in particular, unsubstituted or substitutedacyl, aryl, aralkoxymethyl or aralkyl groups. Since the aminoprotectinggroups are removed after the desired reaction (or reaction sequence),their type and size are furthermore not crucial; however, preference isgiven to those having 1-20, in particular 1-8, carbon atoms. The term“acyl group” is to be understood in the broadest sense in connectionwith the present process. It includes acyl groups derived fromaliphatic, araliphatic, aromatic or heterocyclic carboxylic acids orsulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl andespecially aralkoxycarbonyl groups. Examples of such acyl groups arealkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such asphenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such asPOA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, BOC and 2-iodoethoxycarbonyl;aralkoxycarbonyl, such as CBZ (“carbobenzoxy”),4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr, Pbfand Pmc. Preferred amino-protecting groups are BOC and Mtr, furthermoreCBZ, Fmoc, benzyl and acetyl.

The term “hydroxylprotecting group” is likewise known in general termsand relates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but are easy to remove after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are the above-mentioned unsubstituted orsubstituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.The nature and size of the hydroxylprotecting groups are not crucialsince they are removed again after the desired chemical reaction orreaction sequence; preference is given to groups having 1-20, inparticular 1-10, carbon atoms. Examples of hydroxylprotecting groupsare, inter alia, tert-butoxycarbonyl, benzyl, p-nitrobenzoyl,p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butylare particularly preferred. The COOH groups in aspartic acid andglutamic acid are preferably protected in the form of their tert-butylesters (for example Asp(OBut)).

The compounds of the formula I are liberated from their functionalderivatives—depending on the protecting group used—for example usingstrong acids, advantageously using TFA or perchloric acid, but alsousing other strong inorganic acids, such as hydrochloric acid orsulfuric acid, strong organic carboxylic acids, such as trichloroaceticacid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. Thepresence of an additional inert solvent is possible, but is not alwaysnecessary. Suitable inert solvents are preferably organic, for examplecarboxylic acids, such as acetic acid, ethers, such as tetrahydrofuranor dioxane, amides, such as DMF, halogenated hydrocarbons, such asdichloromethane, furthermore also alcohols, such as methanol, ethanol orisopropanol, and water. Mixtures of the above-mentioned solvents arefurthermore suitable. TFA is preferably used in excess without additionof a further solvent, and perchloric acid is preferably used in the formof a mixture of acetic acid and 70% perchloric acid in the ratio 9:1.The reaction temperatures for the cleavage are advantageously betweenabout 0 and about 50°, preferably between 15 and 30° (room temperature).

The BOC, OBut, Pbf, Pmc and Mtr groups can, for example, preferably becleaved off using TFA in dichloromethane or using approximately 3 to 5NHCl in dioxane at 15-30°, and the FMOC group can be cleaved off using anapproximately 5 to 50% solution of dimethylamine, diethylamine orpiperidine in DMF at 15-30°.

The trityl group is employed to protect the amino acids histidine,asparagine, glutamine and cysteine. They are cleaved off, depending onthe desired end product, using TFA/10% thiophenol, with the trityl groupbeing cleaved off from all the said amino acids; on use of TFA/anisoleor TFA/thioanisole, only the trityl group of His, Asn and Gln is cleavedoff, whereas it remains on the Cys side chain.

The Pbf (pentamethylbenzofuranyl) group is employed to protect Arg. Itis cleaved off using, for example, TFA in dichloromethane.

Hydrogenolytically removable protecting groups (for example CBZ orbenzyl) can be cleaved off, for example, by treatment with hydrogen inthe presence of a catalyst (for example a noble-metal catalyst, such aspalladium, advantageously on a support, such as carbon). Suitablesolvents here are those indicated above, in particular, for example,alcohols, such as methanol or ethanol, or amides, such as DMF. Thehydrogenolysis is generally carried out at temperatures between about 0and 100° and pressures between about 1 and 200 bar, preferably at 20-30°and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, forexample, on 5 to 10% Pd/C in methanol or using ammonium formate (insteadof hydrogen) on Pd/C in methanol/DMF at 20-30°.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate,benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate,camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate,citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine(benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine andtris(hydroxymethyl)methylamine(tromethamine), but this is not intendedto represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

Particular preference is given to hydrochloride, dihydrochloride,hydrobromide, maleate, mesylate, phosphate, sulfate and succinate.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds.

The lubricated mixture is then pressed to give tablets. The compoundsaccording to the invention can also be combined with a free-flowinginert excipient and then pressed directly to give tablets withoutcarrying out the granulation or dry-pressing steps. A transparent oropaque protective layer consisting of a shellac sealing layer, a layerof sugar or polymer material and a gloss layer of wax may be present.Dyes can be added to these coatings in order to be able to differentiatebetween different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa prespecified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and salts, solvates and physiologicallyfunctional derivatives thereof can also be administered in the form ofliposome delivery systems, such as, for example, small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from various phospholipids, such as, forexample, cholesterol, stearylamine or phosphatidylcholines.

The compounds of the formula I and the salts, solvates andphysiologically functional derivatives thereof can also be deliveredusing monoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds can also be coupled to solublepolymers as targeted medicament carriers. Such polymers may encompasspolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention for the treatment of neoplastic growth, for example colon orbreast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound according to the invention per se. Itcan be assumed that similar doses are suitable for the treatment ofother conditions mentioned above.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active ingredient indissolved or lyophilised form.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, especially for humans, in the treatment of tyrosinekinase-induced diseases. These diseases include the proliferation oftumour cells, pathological neovascularisation (or angiogenesis) whichpromotes the growth of solid tumours, ocular neovascularisation(diabetic retinopathy, age-induced macular degeneration and the like)and inflammation (psoriasis, rheumatoid arthritis and the like).

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts and solvates thereoffor the preparation of a medicament for the treatment or prevention ofcancer.

Preferred carcinomas for the treatment originate from the group cerebralcarcinoma, urogenital tract carcinoma, carcinoma of the lymphaticsystem, stomach carcinoma, laryngeal carcinoma and lung carcinoma. Afurther group of preferred forms of cancer are monocytic leukaemia, lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas and breast carcinoma.

Also encompassed is the use of the compounds according to Claim 1according to the invention and/or physiologically acceptable salts andsolvates thereof for the preparation of a medicament for the treatmentor prevention of a disease in which angiogenesis is implicated.

Such a disease in which angiogenesis is implicated is an ocular disease,such as retinal vascularisation, diabetic retinopathy, age-inducedmacular degeneration and the like.

The use of compounds of the formula I and/or physiologically acceptablesalts and solvates thereof for the preparation of a medicament for thetreatment or prevention of inflammatory diseases also falls within thescope of the present invention. Examples of such inflammatory diseasesinclude rheumatoid arthritis, psoriasis, contact dermatitis, delayedhyper-sensitivity reaction and the like.

Also encompassed is the use of the compounds of the formula I and/orphysiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment or prevention of atyrosine kinase-induced disease or a tyrosine kinase-induced conditionin a mammal, in which to this method a therapeutically effective amountof a compound according to the invention is administered to a sickmammal in need of such treatment. The therapeutic amount variesaccording to the specific disease and can be determined by the personskilled in the art without undue effort.

The present invention also encompasses the use compounds of the formulaI and/or physiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment or prevention of retinalvascularisation.

Methods for the treatment or prevention of ocular diseases, such asdiabetic retinopathy and age-induced macular degeneration, are likewisepart of the invention. The use for the treatment or prevention ofinflammatory diseases, such as rheumatoid arthritis, psoriasis, contactdermatitis and delayed hypersensitivity reaction, as well as thetreatment or prevention of bone pathologies from the group osteosarcoma,osteoarthritis and rickets, likewise falls within the scope of thepresent invention.

The expression “tyrosine kinase-induced diseases or conditions” refersto pathological conditions that depend on the activity of one or moretyrosine kinases. Tyrosine kinases either directly or indirectlyparticipate in the signal transduction pathways of a variety of cellularactivities, including proliferation, adhesion and migration anddifferentiation. Diseases associated with tyrosine kinase activityinclude proliferation of tumour cells, pathological neovascularisationthat promotes the growth of solid tumours, ocular neovascularisation(diabetic retinopathy, age-induced macular degeneration and the like)and inflammation (psoriasis, rheumatoid arthritis and the like).

The compounds of the formula I can be administered to patients for thetreatment of cancer, in particular fast-growing tumours.

The invention thus relates to the use of compounds of the formula I, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, for the preparation of amedicament for the treatment of diseases in which the inhibition,regulation and/or modulation of kinase signal transduction plays a role.

Preference is given here to Met kinase.

Preference is given to the use of compounds of the formula I, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios,

for the preparation of a medicament for the treatment of diseases whichare influenced by inhibition of tyrosine kinases by the compoundsaccording to Claim 1.

Particular preference is given to the use for the preparation of amedicament for the treatment of diseases which are influenced byinhibition of Met kinase by the compounds according to Claim 1.

Especial preference is given to the use for the treatment of a diseasewhere the disease is a solid tumour.

The solid tumour is preferably selected from the group of tumours of thelung, squamous epithelium, the bladder, the stomach, the kidneys, ofhead and neck, the oesophagus, the cervix, the thyroid, the intestine,the liver, the brain, the prostate, the urogenital tract, the lymphaticsystem, the stomach and/or the larynx.

The solid tumour is furthermore preferably selected from the group lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas, colon carcinoma and breast carcinoma.

Preference is furthermore given to the use for the treatment of a tumourof the blood and immune system, preferably for the treatment of a tumourselected from the group of acute myeloid leukaemia, chronic myeloidleukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti- tumouragents:

-   (i) antiproliferative/antineoplastic/DNA-damaging agents and    combinations thereof, as used in medical oncology, such as    alkylating agents (for example cis-platin, carboplatin,    cyclophosphamide, nitrogen mustard, melphalan, chloroambucil,    busulphan and nitrosoureas); anti-metabolites (for example    antifolates such as fluoropyrimidines like 5-fluorouracil and    tegafur, raltitrexed, methotrexate, cytosine arabinoside,    hydroxyurea and gemcitabine); antitumour antibiotics (for example    anthracyclines, like adriamycin, bleomycin, doxorubicin, daunomycin,    epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);    antimitotic agents (for example vinca alkaloids, like vincristine,    vinblastine, vindesine and vinorelbine, and taxoids, like taxol and    taxotere); topoisomerase inhibitors (for example    epipodophyllotoxins, like etoposide and teniposide, amsacrine,    topotecan, irinotecan and camptothecin) and cell-differentiating    agents (for example all-trans-retinoic acid, 13-cis-retinoic acid    and fenretinide);-   (ii) cytostatic agents, such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),    oestrogen receptor downregulators (for example fulvestrant),    antiandrogens (for example bicalutamide, flutamide, nilutamide and    cyproterone acetate), LHRH antagonists or LHRH agonists (for example    goserelin, leuprorelin and buserelin), progesterones (for example    megestrol acetate), aromatase inhibitors (for example as    anastrozole, letrozole, vorazole and exemestane) and inhibitors of    5α-reductase, such as finasteride;-   (iii) agents which inhibit cancer cell invasion (for example    metalloproteinase inhibitors, like marimastat, and inhibitors of    urokinase plasminogen activator receptor function);-   (iv) inhibitors of growth factor function, for example such    inhibitors include growth factor antibodies, growth factor receptor    antibodies (for example the anti-erbb2 antibody trastuzumab    [Herceptin™] and the anti-erbbl antibody cetuximab [C225]), farnesyl    transferase inhibitors, tyrosine kinase inhibitors and    serine/threonine kinase inhibitors, for example inhibitors of the    epidermal growth factor family (for example EGFR family tyrosine    kinase inhibitors, such as    N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine    (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis    (2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and    6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine    (CI 1033)), for example inhibitors of the platelet-derived growth    factor family and for example inhibitors of the hepatocyte growth    factor family;-   (v) antiangiogenic agents, such as those which inhibit the effects    of vascular endothelial growth factor, (for example the    anti-vascular endothelial cell growth factor antibody bevacizumab    [Avastin™], compounds such as those disclosed in published    international patent applications WO 97/22596, WO 97/30035, WO    97/32856 and WO 98/13354) and compounds that work by other    mechanisms (for example linomide, inhibitors of integrin αvβ3    function and angiostatin);-   (vi) vessel-damaging agents, such as combretastatin A4 and compounds    disclosed in international patent applications WO 99/02166, WO    00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;-   (vii) antisense therapies, for example those which are directed to    the targets listed above, such as ISIS 2503, an anti-Ras antisense;-   (viii) gene therapy approaches, including, for example, approaches    for replacement of aberrant genes, such as aberrant p53 or aberrant    BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy)    approaches, such as those using cytosine deaminase, thymidine kinase    or a bacterial nitroreductase enzyme, and approaches for increasing    patient tolerance to chemotherapy or radiotherapy, such as    multi-drug resistance gene therapy; and-   (ix) immunotherapy approaches, including, for example, ex-vivo and    in-vivo approaches for increasing the immunogenicity of patient    tumour cells, such as transfection with cytokines, such as    interleukin 2, interleukin 4 or granulocyte-macrophage colony    stimulating factor, approaches for decreasing T-cell anergy,    approaches using transfected immune cells, such as    cytokine-transfected dendritic cells, approaches using    cytokine-transfected tumour cell lines, and approaches using    anti-idiotypic antibodies.

The medicaments from Table 1 below are preferably, but not exclusively,combined with the compounds of the formula I.

TABLE 1 Alkylating agents Cyclophosphamide Lomustine BusulfanProcarbazine Ifosfamide Altretamine Melphalan Estramustine phosphateHexamethylmelamine Mechloroethamine Thiotepa Streptozocin chloroambucilTemozolomide Dacarbazine Semustine Carmustine Platinum agents CisplatinCarboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin(Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson TetraplatinMatthey) Ormiplatin BBR-3464 Iproplatin (Hoffrnann-La Roche) SM-11355(Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-fluorouracilFludarabine Floxuridine Pentostatin 2-chlorodesoxyadenosine Raltitrexed6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-fluorodesoxycytidine Irofulven(MGI Pharrna) Methotrexate DMDC (Hoffmann-La Idatrexate Roche)Ethynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen)inhibitors Epirubicin Exatecan mesylate Etoposide (Daiichi) Teniposideor Quinamed (ChemGenex) mitoxantrone Gimatecan (Sigma-Tau) Irinotecan(CPT-11) Diflomotecan (Beaufour- 7-ethyl-10- Ipsen) hydroxycamptothecinTAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet J-107088(Merck & Co) (TopoTarget) BNP-1350 (BioNumerik) Pixantrone(Novuspharrna) CKD-602 (Chong Kun Rebeccamycin analogue Dang) (Exelixis)KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) Antitumour Dactinomycin(Actinomycin Amonafide antibiotics D) Azonafide Doxorubicin (Adriamycin)Anthrapyrazole Deoxyrubicin Oxantrazole Valrubicin LosoxantroneDaunorubicin Bleomycin sulfate (Daunomycin) (Blenoxan) EpirubicinBleomycinic acid Therarubicin Bleomycin A Idarubicin Bleomycin BRubidazon Mitomycin C Plicamycinp MEN-10755 (Menarini) PorfiromycinGPX-100 (Gem Cyanomorpholinodoxorubicin Pharmaceuticals) Mitoxantron(Novantron) Antimitotic agents Paclitaxel SB 408075 Docetaxel(GlaxoSmithKline) Colchicine E7010 (Abbott) Vinblastine PG-TXL (CellVincristine Therapeutics) Vinorelbine IDN 5109 (Bayer) Vindesine A105972 (Abbott) Dolastatin 10 (NCI) A 204197 (Abbott) Rhizoxin(Fujisawa) LU 223651 (BASF) Mivobulin (Warner- D 24851 (ASTA Medica)Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar)Epothilone B (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik)PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin52 (Eli Lilly) !DN-5109 (Indena) Vinflunine (Fabre) AVLB (PrescientAuristatin PE (Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) BMS247550 (BMS) BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4-prodrug(OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga)CA-4 (OXiGENE) Aromatase Aminoglutethimide Exemestan inhibitorsLetrozole Atamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi)Formestan Thymidylate Pemetrexed (Eli Lilly) Nolatrexed (Eximias)synthase ZD-9331 (BTG) CoFactor ™ (BioKeys) inhibitors DNA antagonistsTrabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (BaxterInternational) International) Apaziquone (Spectrum Albumin + 32P(Isotope Pharmaceuticals) Solutions) O6-benzylguanine Thymectacin(NewBiotics) (Paligent) Edotreotid (Novartis) Farnesyl Arglabin(NuOncology Tipifarnib (Johnson & transferase Labs) Johnson) inhibitorsIonafarnib (Schering- Perillyl alcohol (DOR Plough) BioPharma)BAY-43-9006 (Bayer) Pump inhibitors CBT-1 (CBA Pharma) ZosuquidarTariquidar (Xenova) trihydrochloride (Eli Lilly) MS-209 (Schering AG)Biricodar dicitrate (Vertex) Histone acetyl Tacedinaline (Pfizer)Pivaloyloxymethyl butyrate transferase inhibitors SAHA (Aton Pharma)(Titan) MS-275 (Schering AG) Depsipeptide (Fujisawa) MetalloproteinaseNeovastat (Aeterna Laboratories) CMT-3 (CollaGenex) inhibitorsMarimastat (British Biotech) BMS-275291 (Celltech) RibonucleosideGallium maltolate (Titan) Tezacitabine (Aventis) reductase inhibitorsTriapin (Vion) Didox (Molecules for Health) TNF-alpha Virulizin (LorusTherapeutics) Revimid (Celgene) agonists/ CDC-394 (Celgene) antagonistsEndothelin-A receptor Atrasentan (Abbot) YM-598 (Yamanouchi) antagonistsZD-4054 (AstraZeneca) Retinoic acid receptor Fenretinide (Johnson &Alitretinoin (Ligand) agonists Johnson) LGD-1550 (Ligand)Immunomodulators Interferon Dexosome therapy (Anosys) Oncophage(Antigenics) Pentrix (Australian Cancer GMK (Progenics) Technology)Adenocarcinoma vaccine JSF-154 (Tragen) (Biomira) Cancer vaccine(Intercell) CTP-37 (AVI BioPharma) Norelin (Biostar) JRX-2 (Immuno-Rx)BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics) Synchrovaxvaccines (CTL !3-Alethin (Dovetail) Immuno) CLL-Thera (Vasogen) Melanomavaccine (CTL Immuno) p21-RAS vaccine (Gem- Vax) Hormonal and OestrogensPrednisone antihormonal Conjugated oestrogens Methylprednisolone agentsEthynyloestradiol Prednisolone chlorotrianisene AminoglutethimideIdenestrol Leuprolide Hydroxyprogesterone Goserelin caproate LeuporelinMedroxyprogesterone Bicalutamide Testosterone Flutamide Testosteronepropionate Octreotide Fluoxymesterone Nilutamide MethyltestosteroneMitotan Diethylstilbestrol P-04 (Novogen) Megestrol 2-Methoxyoestradiol(EntreMed) Tamoxifen Arzoxifen (Eli Lilly) Toremofin DexamethasonePhotodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbid agentsTheralux (Theratechnologies) (Yeda) Motexafin-GadoliniumLutetium-Texaphyrin (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosinekinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitorsLeflunomide(Sugen/Pharmacia) CEP-701 (Cephalon) ZDI839 (AstraZeneca)CEP-751 (Cephalon) Erlotinib (Oncogene Science) MLN518 (Millenium)Canertjnib (Pfizer) PKC412 (Novartis) Squalamine (Genaera) Phenoxodiol OSU5416 (Pharmacia) Trastuzumab (Genentech) SU6668 (Pharmacia) C225(ImClone) ZD4190 (AstraZeneca) rhu-Mab (Genentech) ZD6474 (AstraZeneca)MDX-H210 (Medarex) Vatalanib (Novartis) 2C4 (Genentech) PKI166(Novartis) MDX-447 (Medarex) GW2016 (GlaxoSmith- ABX-EGF (Abgenix)Kline) IMC-1C11 (ImClone) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agentsSR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, Sanofi-Synthelabo)BioCryst) Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist,Ribapharm) stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin(RNA synthesis Aventis) inhibitor, Dong-A) CV-247 (COX-2 inhibitor,Tirapazamine (reducing Ivy Medical) agent, SRI International) P54 (COX-2inhibitor, N-Acetylcysteine (reducing Phytopharm) agent, Zambon)CapCell ™ (CYP450 R-Flurbiprofen (NF-kappaB stimulant, Bavarian Nordic)inhibitor, Encore) GCS-IOO (gal3 antagonist, 3CPA (NF-kappaBGlycoGenesys) inhibitor, Active Biotech) G17DT immunogen (gastrinSeocalcitol (vitamin D inhibitor, Aphton) receptor agonist, Leo)Efaproxiral (oxygenator, 131-I-TM-601 (DNA Allos Therapeutics)antagonist, PI-88 (heparanase inhibitor, TransMolecular) Progen)Eflornithin (ODC inhibitor, Tesmilifen (histamine antagonist, ILEXOncology) YM BioSciences) Minodronic acid Histamine (histamine H2(osteoclast inhibitor, receptor agonist, Maxim) Yamanouchi) Tiazofurin(IMPDH inhibitor, Indisulam (p53 stimulant, Ribapharm) Eisai)Cilengitide (integrin antagonist, Aplidin (PPT inhibitor, Merck KGaA)PharmaMar) SR-31747 (IL-1 antagonist, Rituximab (CD20 antibody,Sanofi-Synthelabo) Genentech) CCI-779 (mTOR kinase Gemtuzumab (CD33inhibitor, Wyeth) antibody, Wyeth Ayerst) Exisulind (PDE-V inhibitor,PG2 (haematopoiesis Cell Pathways) promoter, Pharmagenesis) CP-461(PDE-V inhibitor, Immunol ™ (triclosan Cell Pathways) mouthwash, Endo)AG-2037 (GART inhibitor, Triacetyluridine (uridine Pfizer) prodrug,Wellstat) WX-UK1 (plasminogen SN-4071 (sarcoma agent, activatorinhibitor, Wilex) Signature BioScience) PBI-1402 (PMN stimulant,TransMID-107 ™ ProMetic LifeSciences) (immunotoxin, KS Bortezomib(proteasome Biomedix) inhibitor, Millennium) PCK-3145 (apoptosis SRL-172(T-cell stimulant, promoter, Procyon) SR Pharma) Doranidazole (apoptosisTLK-286 (glutathione-S promoter, Pola) transferase inhibitor, Telik)CHS-828 (cytotoxic agent, PT-100 (growth factor Leo) agonist, PointTherapeutics) Trans-retinic acid Midostaurin (PKC inhibitor,(differentiator, NIH) Novartis) MX6 (apoptosis promoter, Bryostatin-1(PKC stimulant, MAXIA) GPC Biotech) Apomine (apoptosis CDA-II (apoptosispromoter, promoter, ILEX Oncology) Everlife) Urocidin (apoptosis SDX-101(apoptosis promoter, promoter, Bioniche) Salmedix) Ro-31-7453 (apoptosisCeflatonin (apoptosis promoter, promoter, La Roche) ChemGenex)Brostallicin (apoptosis promoter, Pharmacia) Alkylating agentsCyclophosphamide Lomustine Busulfan Procarbazine Ifosfamide AltretamineMelphalan Estramustine phosphate Hexamethylmelamine MechloroethamineThiotepa Streptozocin chloroambucil Temozolomide Dacarbazine SemustineCarmustine Platinum agents Cisplatin Carboplatin Oxaliplatin ZD-0473(AnorMED) Spiroplatin Lobaplatin (Aetema) CarboxyphthalatoplatinumSatraplatin (Johnson Tetraplatin Matthey) Ormiplatin BBR-3464 Iproplatin(Hoffrnann-La Roche) SM-11355 (Sumitomo) AP-5280 (Access)Antimetabolites Azacytidine Tomudex Gemcitabine TrimetrexateCapecitabine Deoxycoformycin 5-fluorouracil Fludarabine FloxuridinePentostatin 2-chlorodesoxyadenosine Raltitrexed 6-MercaptopurineHydroxyurea 6-Thioguanine Decitabine (SuperGen) Cytarabine Clofarabine(Bioenvision) 2-fluorodesoxycytidine Irofulven (MGI Pharrna)Methotrexate DMDC (Hoffmann-La Idatrexate Roche) Ethynylcytidine (Taiho)Topoisomerase Amsacrine Rubitecan (SuperGen) inhibitors EpirubicinExatecan mesylate Etoposide (Daiichi) Teniposide or Quinamed (ChemGenex)mitoxantrone Gimatecan (Sigma-Tau) Irinotecan (CPT-11) Diflomotecan(Beaufour- 7-ethyl-10- Ipsen) hydroxycamptothecin TAS-103 (Taiho)Topotecan Elsamitrucin (Spectrum) Dexrazoxanet J-107088 (Merck & Co)(TopoTarget) BNP-1350 (BioNumerik) Pixantrone (Novuspharrna) CKD-602(Chong Kun Rebeccamycin analogue Dang) (Exelixis) KW-2170 (Kyowa Hakko)BBR-3576 (Novuspharrna) Antitumour Dactinomycin (Actinomycin Amonafideantibiotics D) Azonafide Doxorubicin (Adriamycin) AnthrapyrazoleDeoxyrubicin Oxantrazole Valrubicin Losoxantrone Daunorubicin Bleomycinsulfate (Daunomycin) (Blenoxan) Epirubicin Bleomycinic acid TherarubicinBleomycin A Idarubicin Bleomycin B Rubidazon Mitomycin C PlicamycinpMEN-10755 (Menarini) Porfiromycin GPX-100 (GemCyanomorpholinodoxorubicin Pharmaceuticals) Mitoxantron (Novantron)Antimitotic agents Paclitaxel SB 408075 Docetaxel (GlaxoSmithKline)Colchicine E7010 (Abbott) Vinblastine PG-TXL (Cell VincristineTherapeutics) Vinorelbine IDN 5109 (Bayer) Vindesine A 105972 (Abbott)Dolastatin 10 (NCI) A 204197 (Abbott) Rhizoxin (Fujisawa) LU 223651(BASF) Mivobulin (Warner- D 24851 (ASTA Medica) Lambert) ER-86526(Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis)Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilone B(Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel(Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly)!DN-5109 (Indena) Vinflunine (Fabre) AVLB (Prescient Auristatin PE(Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) BMS 247550 (BMS)BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4-prodrug (OXiGENE) BMS 188797(BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga) CA-4 (OXiGENE) AromataseAminoglutethimide Exemestan inhibitors Letrozole Atamestan(BioMedicines) Anastrazole YM-511 (Yamanouchi) Formestan ThymidylatePemetrexed (Eli Lilly) Nolatrexed (Eximias) synthase ZD-9331 (BTG)CoFactor ™ (BioKeys) inhibitors DNA antagonists Trabectedin (PharmaMar)Mafosfamide (Baxter Glufosfamide (Baxter International) International)Apaziquone (Spectrum Albumin + 32P (Isotope Pharmaceuticals) Solutions)O6-benzylguanine Thymectacin (NewBiotics) (Paligent) Edotreotid(Novartis) Farnesyl Arglabin (NuOncology Tipifarnib (Johnson &transferase Labs) Johnson) inhibitors Ionafarnib (Schering- Perillylalcohol (DOR Plough) BioPharma) BAY-43-9006 (Bayer) Pump inhibitorsCBT-1 (CBA Pharma) Zosuquidar Tariquidar (Xenova) trihydrochloride (EliLilly) MS-209 (Schering AG) Biricodar dicitrate (Vertex) Histone acetylTacedinaline (Pfizer) Pivaloyloxymethyl butyrate transferase SAHA (AtonPharma) (Titan) inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa)Metalloproteinase Neovastat (Aeterna CMT-3 (CollaGenex) inhibitorsLaboratories) BMS-275291 (Celltech) Ribonucleoside Marimastat (BritishTezacitabine (Aventis) reductase Biotech) Didox (Molecules forinhibitors Gallium maltolate (Titan) Health) Triapin (Vion) TNF-alphaVirulizin (Lorus Revimid (Celgene) agonists/ Therapeutics) antagonistsCDC-394 (Celgene) Endothelin-A Atrasentan (Abbot) YM-598 (Yamanouchi)receptor ZD-4054 (AstraZeneca) antagonists Retinoic acid Fenretinide(Johnson & Alitretinoin (Ligand) receptor agonists Johnson) LGD-1550(Ligand) Immuno- Interferon Dexosome therapy modulators Oncophage(Antigenics) (Anosys) GMK (Progenics) Pentrix (Australian CancerAdenocarcinoma vaccine Technology) (Biomira) JSF-154 (Tragen) CTP-37(AVI BioPharma) Cancer vaccine (Intercell) JRX-2 (Immuno-Rx) Norelin(Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) Synchrovax vaccines(CTL MGV (Progenics) Immuno) !3-Alethin (Dovetail) Melanoma vaccine (CTLCLL-Thera (Vasogen) Immuno) p21-RAS vaccine (GemVax) Hormonal andOestrogens Prednisone antihormonal Conjugated oestrogensMethylprednisolone agents Ethynyloestradiol Prednisolonechlorotrianisene Aminoglutethimide Idenestrol LeuprolideHydroxyprogesterone Goserelin caproate Leuporelin MedroxyprogesteroneBicalutamide Testosterone Flutamide Testosterone propionate OctreotideFluoxymesterone Nilutamide Methyltestosterone Mitotan DiethylstilbestrolP-04 (Novogen) Megestrol 2-Methoxyoestradiol Tamoxifen (EntreMed)Toremofin Arzoxifen (Eli Lilly) Dexamethasone Photodynamic Talaporfin(Light Sciences) Pd-Bacteriopheophorbid agents Theralux (Yeda)(Theratechnologies) Lutetium-Texaphyrin Motexafin-Gadolinium(Pharmacyclics) (Pharmacyclics) Hypericin Tyrosine kinase Imatinib(Novartis) Kahalide F (PharmaMar) inhibitorsLeflunomide(Sugen/Pharmacia) CEP-701 (Cephalon) ZDI839 (AstraZeneca)CEP-751 (Cephalon) Erlotinib (Oncogene MLN518 (Millenium) Science)PKC412 (Novartis) Canertjnib (Pfizer) Phenoxodiol O Squalamine (Genaera)Trastuzumab (Genentech) SU5416 (Pharmacia) C225 (ImClone) SU6668(Pharmacia) rhu-Mab (Genentech) ZD4190 (AstraZeneca) MDX-H210 (Medarex)ZD6474 (AstraZeneca) 2C4 (Genentech) Vatalanib (Novartis) MDX-447(Medarex) PKI166 (Novartis) ABX-EGF (Abgenix) GW2016 IMC-1C11 (ImClone)(GlaxoSmithKline) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agentsSR-27897 (CCK-A BCX-1777 (PNP inhibitor, inhibitor, Sanofi- BioCryst)Synthelabo) Ranpirnase (ribonuclease Tocladesine (cyclic AMP stimulant,Alfacell) agonist, Ribapharm) Galarubicin (RNA Alvocidib (CDK inhibitor,synthesis inhibitor, Dong- Aventis) A) CV-247 (COX-2 inhibitor,Tirapazamine (reducing Ivy Medical) agent, SRI International) P54 (COX-2inhibitor, N-Acetylcysteine (reducing Phytopharm) agent, Zambon)CapCell ™ (CYP450 R-Flurbiprofen (NF-kappaB stimulant, Bavarian Nordic)inhibitor, Encore) GCS-IOO (gal3 antagonist, 3CPA (NF-kappaBGlycoGenesys) inhibitor, Active Biotech) G17DT immunogen Seocalcitol(vitamin D (gastrin inhibitor, Aphton) receptor agonist, Leo)Efaproxiral (oxygenator, 131-I-TM-601 (DNA Allos Therapeutics)antagonist, PI-88 (heparanase TransMolecular) inhibitor, Progen)Eflornithin (ODC inhibitor, Tesmilifen (histamine ILEX Oncology)antagonist, YM Minodronic acid BioSciences) (osteoclast inhibitor,Histamine (histamine H2 Yamanouchi) receptor agonist, Maxim) Indisulam(p53 stimulant, Tiazofurin (IMPDH Eisai) inhibitor, Ribapharm) Aplidin(PPT inhibitor, Cilengitide (integrin PharmaMar) antagonist, Merck KGaA)Rituximab (CD20 antibody, SR-31747 (IL-1 antagonist, Genentech)Sanofi-Synthelabo) Gemtuzumab (CD33 CCI-779 (mTOR kinase antibody, WyethAyerst) inhibitor, Wyeth) PG2 (haematopoiesis Exisulind (PDE-Vinhibitor, promoter, Pharmagenesis) Cell Pathways) Immunol ™ (triclosanCP-461 (PDE-V inhibitor, mouthwash, Endo) Cell Pathways)Triacetyluridine (uridine AG-2037 (GART inhibitor, prodrug, Wellstat)Pfizer) SN-4071 (sarcoma agent, WX-UK1 (plasminogen SignatureBioScience) activator inhibitor, Wilex) TransMID-107 ™ PBI-1402 (PMNstimulant, (immunotoxin, KS ProMetic LifeSciences) Biomedix) Bortezomib(proteasome PCK-3145 (apoptosis inhibitor, Millennium) promoter,Procyon) SRL-172 (T-cell stimulant, Doranidazole (apoptosis SR Pharma)promoter, Pola) TLK-286 (glutathione-S CHS-828 (cytotoxic agent,transferase inhibitor, Telik) Leo) PT-100 (growth factor Trans-retinicacid agonist, Point (differentiator, NIH) Therapeutics) MX6 (apoptosispromoter, Midostaurin (PKC inhibitor, MAXIA) Novartis) Apomine(apoptosis Bryostatin-1 (PKC promoter, ILEX Oncology) stimulant, GPCBiotech) Urocidin (apoptosis CDA-II (apoptosis promoter, Bioniche)promoter, Everlife) Ro-31-7453 (apoptosis SDX-101 (apoptosis promoter,La Roche) promoter, Salmedix) Brostallicin (apoptosis Ceflatonin(apoptosis promoter, Pharmacia) promoter, ChemGenex)

A combined treatment of this type can be achieved with the aid ofsimultaneous, consecutive or separate dispensing of the individualcomponents of the treatment. Combination products of this type employthe compounds according to the invention.

Assays

The compounds of the formula I described in the examples were tested bythe assays described below and were found to have kinase inhibitoryactivity. Other assays are known from the literature and could readilybe performed by the person skilled in the art (see, for example,Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol. Chem.274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk etal., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst.52:413-427; Nicosia et al., In Vitro 18:538- 549).

Measurement of Met Kinase Activity

According to the manufacturer's data (Met, active, upstate, catalogueNo. 14-526), Met kinase is expressed for the purposes of proteinproduction in insect cells (Sf21; S. frugiperda) and subsequentaffinity-chromatographic purification as “N-terminal 6His-tagged”recombinant human protein in a baculovirus expression vector.

The kinase activity can be measured using various available measurementsystems. In the scintillation proximity method (Sorg et al., J. ofBiomolecular Screening, 2002, 7, 11-19), the flashplate method or thefilter binding test, the radioactive phosphorylation of a protein orpeptide as substrate is measured using radioactively labelled ATP(³²P-ATP, ³³P-ATP). In the case of the presence of an inhibitorycompound, a reduced radioactive signal, or none at all, can be detected.Furthermore, homogeneous time-resolved fluorescence resonance energytransfer (HTR-FRET) and fluoroescence polarisation (FP) technologies canbe used as assay methods (Sills et al., J. of Biomolecular Screening,2002, 191-214).

Other non-radioactive ELISA assay methods use specificphospho-antibodies (phospho-ABs). The phospho-antibody only binds thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated antibody (Ross etal., 2002, Biochem. J.).

Flashplate Method (Met Kinase)

The test plates used are 96-well Flashplate® microtitre plates fromPerkin Elmer (Cat. No. SMP200). The components of the kinase reactiondescribed below are pipetted into the assay plate. The Met kinase andthe substrate poly Ala-Glu-Lys-Tyr, (pAGLT, 6:2:5:1), are incubated for3 hrs at room temperature with radioactively labelled ³³P-ATP in thepresence and absence of test substances in a total volume of 100 μl. Thereaction is terminated using 150 μl of a 60 mM EDTA solution. Afterincubation for a further 30 min at room temperature, the supernatantsare filtered off with suction, and the wells are washed three times with200 μl of 0.9% NaCl solution each time. The measurement of the boundradioactivity is carried out by means of a scintillation measuringinstrument (Topcount NXT, Perkin-Elmer).

The full value used is the inhibitor-free kinase reaction. This shouldbe approximately in the range 6000-9000 cpm. The pharmacological zerovalue used is staurosporin in a final concentration of 0.1 mM. Theinhibitory values (IC50) are determined using the RS1_MTS program.

Kinase reaction conditions per well:

-   30 μl of assay buffer-   10 μl of substance to be tested in assay buffer with 10% of DMSO-   10 μl of ATP (final concentration 1 μM cold, 0.35 μCi of ³³P-ATP)-   50 μl of Met kinase/substrate mixture in assay buffer;    -   (10 ng of enzyme/well, 50 ng of pAGLT/well)    -   Solutions used:    -   Assay buffer:    -   50 mM HEPES        -   3 mM magnesium chloride        -   3 μM sodium orthovanadate        -   3 mM manganese(II) chloride        -   1 mM dithiothreitol (DTT)    -   pH=7.5 (to be set using sodium hydroxide)    -   Stop solution:    -   60 mM Titriplex III (EDTA)    -   ³³P-ATP: Perkin-Elmer;    -   Met kinase: Upstate, Cat. No. 14-526, Stock 1 μg/10 μl; spec.        activity 954 U/mg;    -   Poly-Ala-Glu-Lys-Tyr, 6:2:5:1:Sigma Cat. No. P1152

In-Vivo Tests

Experimental procedure: Female Balb/C mice (breeder: Charles River Wiga)were 5 weeks old on arrival. They were acclimatised to our keepingconditions for 7 days. Each mouse was subsequently injectedsubcutaneously in the pelvic area with 4 million TPR-Met/NIH3T3 cells in100 μl of PBS (without Ca++ and Mg++). After 5 days, the animals wererandomised into 3 groups, so that each group of 9 mice had an averagetumour volume of 110 μl (range: 55-165). 100 μl of vehicle (0.25%methylcellulose/100 mM acetate buffer, pH 5.5) were administered dailyto the control group, and 200 mg/kg of “A56” or “A91” dissolved in thevehicle (volume likewise 100 μl/animal) were administered daily to thetreatment groups, in each case by gastric tube. After 9 days, thecontrols had an average volume of 1530 μl and the experiment wasterminated.

Measurement of the tumour volume: The length (L) and breadth (B) weremeasured using a Vernier calliper, and the tumour volume was calculatedfrom the formula L×B×B/2.

Keeping conditions: 4 or 5 animals per cage, feeding with commercialmouse food (Sniff).

The compounds “A18” and “A22” have a significant antitumoural action.

Above and below, all temperatures are indicated in° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the residue is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent: ethyl acetate/methanol 9:1.

-   Mass spectrometry (MS): EI (electron impact ionisation) M⁺    -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺-   APCl-MS (atmospheric pressure chemical ionisation—mass spectrometry)    (M+H)⁺.-   Mass spectrometry (MS): El (electron impact ionisation) M⁺    -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺-   APCI-MS (atmospheric pressure chemical ionisation—mass spectrometry)    (M+H)⁺.    HPLC/MS Analyses

are carried out in a 3μ Silica-Rod column with a 210 second gradientfrom 20 to 100% water/acetonitrile/0.01% of trifluoroacetic acid, at aflow rate of 2.2 ml/min, and detection at 220 nm.

HPLC Analyses (Method A)

-   Column: Chromolith RP18e 100*3 mm-   Flow rate: 2 ml/min-   Solvent A: H₂O+0.1% of trifluoroacetic acid-   Solvent B: acetonitrile+0.1% of trifluoroacetic acid-   Gradient 5 min-   0-4 min: 99:1→1:99-   4-5 min: 1:99-1:99    HPLC Analyses (Method B)-   Column: Chromolith RP18e 100*3 mm-   Flow rate: 4 ml/min-   Solvent A: H₂O+0.05% of HCOOH-   Solvent B: acetonitrile+10% of solvent A-   Gradient 8 min-   0-1 min: 99:1→99:1-   1-7 min: 99:1→1:99-   7-8 min: 1:99→1:99    HPLC Analysis (Method C)-   Flow rate: 2 ml/min-   99:01-0:100 water+0.1% (vol.) of TFA:acetonitrile+0.1% (vol.) of TFA-   0.0 to 0.2 min: 99:01-   0.2 to 3.8 min: 99:01→0:100-   3.8 to 4.2 min: 0:100-   Column: Chromolith Performance RP18e; 100 mm long, internal diameter    3 mm, wavelength: 220 nm

Retention time Rt in minutes [min].

Examples of the Preparation of the Pyradizinone Starting Compounds

The pyridazinones are generally prepared by processes from W. H. Coates,A. McKillop, Synthesis 1993, p. 334.

An example thereof is the synthesis of3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile:

927 g (10.6 mol) of glyoxylic acid monohydrate are introduced inportions into a solution of 1278 g (8.80 mol) of 3-acetylbenzonitrile in1.5 l of acetic acid. The resultant solution is heated at 95° C. for 18hours. The mixture is allowed to cool to 30° C., and 7 l of water and899 ml (18.5 mol) of hydrazinium hydroxide are added successively. Thereaction mixture is stirred at 95° C. for 4 hours. The mixture isallowed to cool to 60° C., and the resultant precipitate is filtered offwith suction and washed with 5 l of water and 2 l of acetone. Theresidue is heated to the boil in 5 l of acetone and filtered off withsuction while hot. 5 l of acetic acid are added to the residue, and themixture is heated at 90° C. for 2 hours with stirring. The mixture isallowed to cool to room temperature, and the residue is filtered offwith suction and washed with acetone. The residue is again heated to 90°C. with 5 I of acetic acid, cooled to room temperature, filtered offwith suction and washed with acetone. The residue is dried in vacuo:3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile as beige crystals; ESI198.

Some pyridazinones can be prepared in accordance with A. J. Goodman etal., Tetrahedron 55 (1999), 15067-15070. An example thereof is thealternative synthesis of3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile:

2.70 kg (18.0 mol) of sodium iodide are added in portions at roomtemperature to a mixture of 5.0 l of water and 11.3 l of 57% aqueoushydroiodic acid (75.2 mol). 2.00 kg (13.4 mol) of 3,6-dichloropyridazineare subsequently added in portions to the solution held at 20° C. Thereaction mixture is stirred at 20° C. for 18 hours. 10 l of tert-butylmethyl ether and 4 l of water are added to the reaction mixture. Theorganic phase is separated off and washed with water and aqueous sodiumsulfite solution. The organic phase is concentrated, heptane is added,and the resultant solid is filtered off with suction and washed withheptane. The residue is dried in vacuo: 3-chloro-6-iodopyridazine ascolourless leaf-shaped crystals; ESI 241.

A solution of 212 mg (2.0 mmol) of sodium carbonate in 1 ml of water isadded to a solution, kept under nitrogen, of 240 mg (1.00 mmol) of3-chloro-6-iodopyridazine in 1 ml of toluene, and the mixture is heatedto 80° C. 7.0 mg (0.010 mmol) of bis(triphenylphosphine)palladium(II)chloride are added, and a solution of 147 mg (1.00 mmol) of3-cyanobenzeneboronic acid is subsequently added dropwise. The reactionmixture is stirred at 80° C. for 18 hours. The reaction mixture iscooled to room temperature, water is added, and the solid is filteredoff with suction and washed with water. The residue is dried in vacuo:3-(6-chloropyridazin-3-yl)benzonitrile as colourless crystals; ESI 216.

A suspension of 85 mg (0.396 mol) of3-(6-chloropyridazin-3-yl)benzonitrile in 0.5 ml of acetic acid isheated to 80° C. and stirred at this temperature for 24 hours. Thereaction mixture is cooled to room temperature, water is added, and thesolid is filtered off with suction. The residue is washed with water anddried in vacuo: 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile ascolourless crystals.

The following pyridazinones are preferably prepared by this process:

Some pyridazinones are prepared by the following process. An examplethereof is the synthesis of6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one:

705 g (3.39 mol) of 1-methyl-1H-pyrazole-4-boronic acid pinacol esterand 1.44 kg of tripotassium phosphate trihydrate are added to a solutionof 815 g (3.39 mol) of 3-chloro-6-iodopyridazine in 3.8 l of1,2-dimethoxyethane. The resultant suspension is heated to 80° C. undernitrogen and with stirring, and 59.5 g (85 mmol) ofbis(triphenylphosphine)palladium(II) chloride are added. The reactionmixture is stirred at 80° C. for 3 hours. The mixture is allowed to coolto room temperature, and 9 l of water are added. The resultantprecipitate is filtered off with suction, washed with water and dried invacuo: 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine as browncrystals; ESI 195.

A suspension of 615 g (2.90 mol) of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine in a mixture of 1.86 lof formic acid and 2.61 l of water is heated to 80° C. with stirring andstirred at this temperature for 28 hours. The reaction mixture is cooledto room temperature, a little activated carbon is added, and the solidis filtered off with suction. The filtrate is adjusted to a pH of 7using 40% aqueous sodium hydroxide solution with ice cooling and left at6° C. for 16 h. The resultant precipitate is filtered off with suction,washed with water and dried in vacuo:6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one as colourless crystals;ESI 177.

The following pyridazinones are preferably prepared by this process:

Preparation of 6-(5-methyloxazol-2-yl)-2H-pyridazin-3-one

10.6 g (69.2 mmol) of 1-hydroxybenzotriazole hydrate and 17.3 g ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride are addedto a solution of 10.0 g (69.2 mmol) of6-oxo-1,6-dihydropyridazine-3-carboxylic acid monohydrate and 3.85 g(69.2 mmol) of propargylamine in 200 ml of DMF, and the resultantsolution is stirred at room temperature for 18 hours. The reactionmixture is partitioned between water and dichloromethane. The organicphase is washed with saturated sodium hydrogencarbonate solution, driedover sodium sulfate and evaporated:N-prop-2-ynyl-6-oxo-1,6-dihydropyridazine-3-carboxamide as colourlesscrystals; ESI 178.

622 mg (2.05 mmol) of gold(III) chloride are added to a solution of 3.69g (20.5 mmol) of N-prop-2-ynyl-6-oxo-1,6-dihydropyridazine-3-carboxamidein 41 ml of acetonitrile, and the mixture is stirred at room temperaturefor 3 days. A further 622 mg (2.05 mmol) of gold(III) chloride areadded, and the mixture is stirred at room temperature for 7 days. Thereaction mixture is evaporated and chromatographed on a silica gelcolumn with dichloromethane/methanol as eluent:6-(5-methyloxazol-2-yl)-2H-pyridazin-3-one as yellowish crystals; ESI178.

Preparation of6-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2H-pyridazin-3-one

Preparation of tert-butyl4-(6-oxo-1,6-dihydropyridazin-3-yl)piperazine-1-carboxylate

1 g (4.62 mmol) of 6-piperazin-1-yl-2H-pyridazin-3-one hydrochloride(Eur. J. Med. Chem. 1992, 27, 545-549) is suspended in 10 ml of THF, and1.34 ml (9.69 mmol) of triethylamine and 1.09 ml (5.08 mmol) ofdi-tert-butyl dicarbonate are added. The mixture is stirred at RT for 15h, and the solvent is removed. Ethyl acetate and water are added to theresidue. A white solid remains undissolved. The residue is filtered offwith suction and washed with water and ethyl acetate and dried in vacuo;yield 0.9 g; HPLC: Rt=2.27 min (method B); HPLC-MS: 281 (M+H).

Preparation of 6-(5-methyl-1,2,4-oxadiazol-3-yl)-2H-pyridazin-3-one

20 g (125 mmol) of 6-oxo-1,6-dihydropyridazine-3-carboxylic acid hydrateare suspended in 400 ml of methanol, and 10.7 ml (147 mmol) of thionylchloride are slowly added with ice cooling. The suspension is stirred at70° C. for 15 h, during which everything dissolves. The reaction mixtureis concentrated to about 100 ml, during which a white precipitate forms.This precipitate is filtered off with suction and washed with methanoland dried in vacuo. Yield 19.2 g; HPLC: Rt=1.27 min (method B); HPLC-MS:155 (M+H).

19.27 g (125 mmol) of methyl 6-oxo-1,6-dihydropyridazine-3-carboxylateare dissolved in 300 ml of ammoniacal methanol, and the mixture isstirred at room temperature for 16 h. The solvent is removed, and theresidue is reacted further without further work-up; yield 16.5 g.

15 g (108 mmol) of 6-oxo-1,6-dihydropyridazine-3-carboxamide aresuspended in 200 ml of dichloromethane. The suspension is cooled to 0°C., and 45 ml of pyridine and 18 ml (129 mmol) of trifluoroaceticanhydride are subsequently added dropwise. The mixture is stirred at RTfor 5 days. 400 ml of water are added to the suspension, which is thenextracted with 3×300 ml of DCM. The combined organic phases are driedusing sodium sulfate and evaporated to dryness. A precipitate forms inthe filtrate. This precipitate is filtered off with suction, washed withwater and dried in vacuo. The aqueous phase is saturated with sodiumchloride and extracted with 3×300 ml of ethyl acetate. The organic phaseis dried and evaporated. All 3 fractions are combined and reactedfurther without further purification; yield: 14.3 g; GC-MS: 121 (M⁺).

1 g (8.26 mmol) of 6-oxo-1,6-dihydropyridazine-3-carbonitrile and 2.87 g(41.3 mmol) of hydroxylammonium chloride are suspended in 200 ml ofethanol, and 5.7 ml (41.3 mmol) of triethylamine are added. The reactionmixture is stirred at room temperature for 5 days. The solvent isremoved, and the residue is stirred with water, filtered and dried;yield: 754 mg, red-brown solid; LC-MS: 155 (M+H).

2.8 ml of glacial acetic acid, 2.3 ml of acetic anhydride and 200 μl ofpyridine are added to 375 mg (2.43 mmol) ofN-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxamidine, and the mixtureis stirred at 90° C. for 15 h. During cooling of the reaction mixture, aprecipitate forms, which is filtered off with suction, washed with waterand dried in vacuo; yield: 253 mg, yellow solid; HPLC: Rt=1.51 min;LC-MS: 179 (M+H).

EXAMPLE 1

The preparation of2-[3-(5-methylpyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one(“A1”) is carried out analogously to the following scheme

1.1 6.52 g (20 mmol) of caesium carbonate are added to a solution of4.52 g (20 mmol) of 6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one and5.06 g (20 mmol) of 3-(3-bromomethylphenyl)-5-methyl-1,2,4-oxadiazole(prepared by the method of W. W. K. R. Mederski et al, Tetrahedron 55,1999, 12757-12770) in 40 ml of 1-methylpyrrolidinone (NMP), and theresultant suspension is stirred at room temperature for 18 hours. Wateris added to the reaction mixture, and the resultant precipitate isfiltered off, washed with water and dried. The crude product isrecrystallised from 2-propanol:6-(3,4,5-trifluorophenyl)-2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2H-pyridazin-3-oneas pale-yellowish crystals; ESI 399.

1.2 2 ml of acetic acid, 2 ml of water and 6 g of Raney nickel are addedto a solution of 6.00 g (14.9 mmol) of6-(3,4,5-trifluorophenyl)-2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2H-pyridazin-3-onein 60 ml of methanol, and the mixture is hydrogenated at roomtemperature and atmospheric pressure for 44 hours. The reaction mixtureis filtered, and the filtrate is evaporated. The crystalline residue isboiled in tert-butyl methyl ether. The mixture is allowed to cool, andthe solid is filtered off with suction and washed with tert-butyl methylether. The residue is dried in vacuo: and allowed to cool.3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-yl-methyl]benzamidiniumacetate as colourless crystals; ESI 359.

3-[6-Oxo-3-(3,5-difluorophenyl)-6H-pyridazin-1-ylmethyl]benzamidiniumacetate, colourless crystals, is prepared analogously; ESI 341.

1.3 1.31 ml (11.0 mmol) of 3-ethoxymethacrolein and 2.04 ml (11.0 mmol)of a 30% sodium methoxide solution in methanol are added to a suspensionof 4.18 g (10.0 mmol) of3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]benzamidiniumacetate in 40 ml of methanol, and the mixture is heated at 50° C. for 18hours. The mixture is allowed to cool, and the resultant precipitate isfiltered off with suction, washed with methanol and dried in vacuo:2-[3-(5-methylpyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one(“A1”) as colourless crystals; ESI 409; ¹H-NMR (DMSO-d₆): δ [ppm]=2.32(s, 3H), 5.45 (s, 2H), 7.16 (d, J=9.5 Hz, 1H), 7.52 (m, 2H), 7.90 (m,2H), 8.13 (d, J =9.5 Hz, 1H), 8.30 (dt, J₁=7.5 Hz, J₂=1.5 Hz, 1H), 8.46(t, J=1.5 Hz, 1H), 8.75 (s, 2H).

Analogous reaction of the benzamidinium acetate with4-trimethylsilyl-3-butyn-1-one with potassium carbonate/acetonitrile at120° C. in the microwave gives the following compounds

-   -   6-(3,5-difluorophenyl)-2-[3-(5-methylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one        (“A2”), ESI 391;    -   2-[3-(4-methylpyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one        (“A3”), ESI 409.

Heating of the benzamidinium acetate at 175° C. with malondialdehydebis-dimethyl acetal in an analogous manner gives the compound

-   -   2-(3-pyrimidin-2-ylbenzyl)-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one        (“A4”), ESI 395.

EXAMPLE 2

The preparation of4-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}morpholin-3-one(“A5”) is carried out analogously to the following scheme

2.1 2.83 g (22.5 mmol) of 3-aminobenzyl alcohol and 5.96 g (22.5 mmol)of triphenylphosphine are added to a suspension, kept under nitrogen, of3.12 g (15.0 mmol) of 6-(3,5-difluorophenyl)-2H-pyridazin-3-one in 80 mlof THF, and the mixture is stirred at room temperature for 30 minutes.The suspension is cooled to 0° C., and 4.65 ml (22.5 mmol) ofdiisopropyl azodicarboxylate (DIAD) are added dropwise. The reactionmixture is stirred at room temperature for 18 hours. The reactionmixture is evaporated, and the residue is heated in 50 ml of isopropanoland allowed to cool. The resultant precipitate is filtered off withsuction, washed with isopropanol and tert-butyl methyl ether and driedin vacuo: 2-(3-aminobenzyl)-6-(3,5-difluorophenyl)-2H-pyridazin-3-one ascolourless crystals; ESI 314.

2.2 235 mg (1.5 mmol) of (2-chloroethoxy)acetyl chloride are added to asuspension 313 mg (1.00 mmol) of2-(3-aminobenzyl)-6-(3,5-difluorophenyl)-2H-pyridazin-3-one in 2 ml oftoluene, and the mixture is heated at the boil for 18 hours. The mixtureis allowed to cool, and the resultant precipitate is filtered off withsuction, washed with tert-butyl methyl ether and dried in vacuo:2-(2-chloroethoxy)-N-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}acetamideas colourless crystals; ESI 434.

2.3 509 mg (1.56 mmol) of caesium carbonate are added to a solution of339 mg (0.78 mmol) of2-(2-chloroethoxy)-N-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}acetamidein 2 ml of acetonitrile, and the mixture is stirred at room temperaturefor 18 hours. The reaction mixture is filtered, and the filtrate isevaporated. The residue is taken up in tert-butyl methyl ether, filteredoff with suction and washed with tert-butyl methyl ether:4-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}morpholin-3-one(“A5”) as colourless crystals; ESI 398.

Analogous reaction of the aniline derivatives with 3-chloropropylchloroformate gives the following compounds:

-   -   3-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}-1,3-oxazinan-2-one

-   -   3-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}-1,3-oxazinan-2-one        (“A7”), ESI 416.

EXAMPLE 3

The preparation of1-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}-3-methyl-6H-pyridazin-6-one(“A8”) is carried out analogously to the following scheme

3.1 5.03 g (21.1 mmol) of 3-iodobenzyl alcohol and 5.55 g (20.9 mmol) oftriphenylphosphine are added to a suspension, kept under nitrogen, of2.92 g (14.0 mmol) of 6-(3,5-difluorophenyl)-2H-pyridazin-3-one in 100ml of THF, and the mixture is stirred at room temperature for 30minutes. The suspension is cooled to 0° C., and 4.33 ml (20.9 mmol) ofdiisopropyl azodicarboxylate are added dropwise. The reaction mixture isstirred at room temperature for 1.5 hours. The reaction mixture isevaporated, and the residue is heated in 50 ml of isopropanol andallowed to cool. The resultant precipitate is filtered off with suction,washed with isopropanol and petroleum ether and dried in vacuo:6-(3,5-difluorophenyl)-2-(3-iodobenzyl)-2H-pyridazin-3-one as colourlesscrystals; ESI 425.

3.2 14.3 mg (0.08 mmol) of copper(I) iodide, 76 mg (0.55 mmol) ofpotassium carbonate and 11 mg (0.08 mmol) of 8-hydroxyquinoline areadded to a solution of 212 mg (0.50 mmol) of6-(3,5-difluorophenyl)-2-(3-iodobenzyl)-2H-pyridazin-3-one and 55.1 mg(0.5 mmol) of 6-methylpyridazin-3(2H)-one in 2 ml of DMF, and themixture is heated at 120° C. for 24 hours. The reaction mixture isallowed to cool, and 10% aqueous ammonia solution and ethyl acetate areadded. The resultant precipitate is filtered off with suction, washedwith water and dried. The residue is boiled in ethyl acetate, filteredoff with suction and washed with ethyl acetate. The residue is dried invacuo:1-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}-3-methyl-6H-pyridazin-6-one(“A8”) as brownish crystals; ESI 407.

EXAMPLE 4

The preparation of6-(3,5-difluorophenyl)-2-[3-(5-methylpyridin-2-yl)benzyl]-2H-pyridazin-3-one(“A9”) is carried out analogously to the following scheme

4.1 92 mg (0.08 mmol) of tetrakis(triphenylphosphine)palladium are addedto a suspension, kept under nitrogen, of 849 mg (4.0 mmol) oftripotassium phosphate, 344 mg (2.0 mmol) of 2-bromo-5-methylpyridineand 304 mg (2.0 mmol) of 3-hydroxymethylbenzeneboronic acid in 12 ml ofdioxane and 1 ml of water, and the mixture is heated at the boil withstirring for 18 hours. The reaction mixture is cooled to roomtemperature and partitioned between water and ethyl acetate. The organicphase is dried over sodium sulfate and evaporated, and the residue ischromatographed on a silica gel column with dichloromethane/methanol aseluent: [3-(5-methylpyridin-2-yl)phenyl]methanol as yellowish oil; ESI200.

4.2 134 mg (0.66 mmol) of diisopropyl azodicarboxylate are added to asolution of 88 mg (0.44 mmol) of[3-(5-methylpyridin-2-yl)phenyl]methanol, 138 mg (0.66 mmol) of6-(3,5-difluorophenyl)-2H-pyridazin-3-one and 174 mg (0.66 mmol) oftriphenylphosphine in 3.5 ml of THF. The reaction mixture is stirred atroom temperature for 18 hours. The mixture is evaporated, and theresidue is chromatographed on a silica gel column withdichloromethane/methanol as eluent:6-(3,5-difluorophenyl)-2-[3-(5-methylpyridin-2-yl)benzyl]-2H-pyridazin-3-one(“A9”) as colourless crystals; ESI 390.

The following compounds are obtained analogously

-   -   6-(3,5-difluorophenyl)-2-[3-(5-methoxypyridin-2-yl)benzyl]-2H-pyridazin-3-one

EXAMPLE 5

The preparation of2-[3-(5-aminopyridin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one(“A11”) and of6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]benzyl}-2H-pyridazin-3-one(“A12”) is carried out analogously to the following scheme

5.1 A suspension, kept under nitrogen, of 3.69 g (18.2 mmol) of2-bromo-5-nitropyridine, 840 mg (0.73 mmol) oftetrakis(triphenylphosphine)palladium and 3.55 g (33.4 mmol) of sodiumcarbonate in 133 ml of toluene is heated to the boil. A solution of 5.07g (32.7 mmol) of 3-(hydroxymethyl)benzeneboronic acid in 133 ml oftoluene is then added dropwise, and the reaction mixture is heated atthe boil for 18 hours. Water is added to the reaction mixture. Theorganic phase is separated off, and the aqueous is extracted a number oftimes with toluene. The combined organic phases are dried over sodiumsulfate and evaporated. The residue is chromatographed on a silica gelcolumn with dichloromethane/methanol:

-   [3-(5-nitropyridin-2-yl)phenyl]methanol as yellow crystals; ESI 231.

5.2 4.46 g (22.0 mmol) of diisopropyl azodicarboxylate are addeddropwise to a solution of 3.37 g (14.7 mmol) of[3-(5-nitropyridin-2-yl)phenyl]-methanol, 4.58 g (22.0 mmol) of6-(3,5-difluorophenyl)-2H-pyridazin-3-one and 5.77 g (22.0 mmol) oftriphenylphosphine in 120 ml of THF, and the reaction mixture is stirredat room temperature for 18 hours. The resultant precipitate is filteredoff with suction, washed with THF and dried in vacuo:6-(3,5-difluorophenyl)-2-[3-(5-nitropyridin-2-yl)benzyl]-2H-pyridazin-3-oneas yellowish crystals; ESI 421.

5.3 220 μl of 2 N hydrochloric acid are added to a suspension of 420 mg(1.00 mmol) of6-(3,5-difluorophenyl)-2-[3-(5-nitropyridin-2-yl)benzyl]-2H-pyridazin-3-onein 4 ml of ethanol, and the mixture is heated to 95° C. and cooled toroom temperature. 402 mg (7.2 mmol) of iron powder is added, and thereaction mixture is stirred at 85° C. for 1 hour and at 60° C. for 17hours. The reaction mixture is filtered, and the filtrate is partitionedbetween water and ethyl acetate. The organic phase is washedsuccessively with sodium hydrogencarbonate solution, sodium carbonatesolution and sodium chloride solution, dried over sodium sulfate andevaporated:2-[3-(5-aminopyridin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one(“A11”) as brownish foam; ESI 391.

5.4 The final step is carried out analogously to Example 9.3, giving6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]benzyl}-2H-pyridazin-3-one(“A12”).

EXAMPLE 6

The preparation of6-(3,5-difluorophenyl)-2-[3-(4-piperazin-1-ylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one(“A13”) is carried out analogously to the following scheme

6.1 A catalyst solution prepared by reaction of of 56 mg (0.08 mmol) ofbis(triphenylphosphine)palladium(II) chloride and 3.0 mg (0.08 mmol) ofsodium borohydride in 0.4 ml of THF at 55° C. is added to a suspension,kept under nitrogen, of 849 mg (4.0 mmol) of tripotassium phosphate, 598mg (2.0 mmol) of tert-butyl4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate (prepared inaccordance with WO 03104225) and 304 mg (2.0 mmol) of3-hydroxymethylbenzeneboronic acid in 12 ml of dioxane and 1 ml ofwater. The reaction mixture is stirred at 97° C. for 18 hours. Thereaction mixture is cooled and partitioned between water and ethylacetate. The organic phase is dried over sodium sulfate and evaporated,and the residue is chromatographed on a silica gel column withdichloromethane/methanol as eluent: tert-butyl4-[2-(3-hydroxymethylphenyl)pyrimidin-4-yl]-piperazine-1-carboxylate asyellowish solid; ESI 371.

6.2 118 mg (0.582 mmol) of diisopropyl azodicarboxylate are added to asolution of 144 mg (0.388 mmol) of tert-butyl4-[2-(3-hydroxymethylphenyl)pyrimidin-4-yl]piperazine-1-carboxylate, 122mg (0.582 mmol) of 6-(3,5-difluorophenyl)-2H-pyridazin-3-one and 153 mg(0.582 mmol) of triphenylphosphine in 3 ml of THF. The reaction mixtureis stirred at room temperature for 18 hours. The mixture is evaporated,and the residue is chromatographed on a silica gel column withdichloromethane/methanol as eluent: tert-butyl4-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}pyrimidin-4-yl)piperazine-1-carboxylateas yellowish oil; ESI 561.

6.3 1.3 ml of 4 N HCl in dioxane are added to a solution of 81 mg (0.14mmol) of tert-butyl4-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-4-yl)piperazine-1-carboxylatein 1 ml of dioxane, and the mixture is left at room temperature for 18hours. The reaction mixture is partitioned between water and ethylacetate. The aqueous phase is adjusted to a pH of 14 using 1 N NaOH andextracted with ethyl acetate. The organic phase is dried over sodiumsulfate and evaporated:6-(3,5-difluorophenyl)-2-[3-(4-piperazin-1-ylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one(“A13”) hydrochloride as colourless amorphous solid; ESI 461.

The following compound is obtained analogously

-   -   6-(3,5-difluorophenyl)-2-{3-[4-(methylpiperidin-4-ylamino)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

EXAMPLE 7

The preparation of6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-yl-methyl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“A14”) is carried out analogously to the following scheme

7.1 12.0 ml (31.5 mmol) of a 20% solution of sodium ethoxide in ethanolare added to a suspension, kept under nitrogen, of 4.00 g (10.0 mmol) of3-[6-oxo-3-(3,5-difluorophenyl)-6H-pyridazin-1-ylmethyl]benzamidiniumacetate and 4.64 g (13.0 mmol) of2-dimethylaminomethylene-1,3-bis-(dimethylimmonio)propanebistetrafluoroborate (prepared by the method of P. J. Coleman et al., J.Med. Chem. 2004, 47, 4829-4837) in 280 ml of ethanol, and the mixture isheated at the boil for 2 hours. The reaction mixture is cooled,evaporated in vacuo and digested with water. The resultant precipitateis filtered off with suction and washed with water. The residue ischromatographed on a silica gel column with dichloromethane/methanol:2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidine-5-carbaldehydeas colourless crystals; ESI 405.

7.2 A suspension of 472 mg (1.17 mmol) of2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carbaldehydein 5 ml of dichloromethane is given succesively with 166 μl of1-methylpiperazine, 495 mg (2.34 mmol) of sodium triacetoxyborohydrideand 67 μl of acetic acid, and the reaction mixture is stirred at roomtemperature for 42 hours. The reaction mixture is partitioned betweendichloromethane and 1 N NaOH. The organic phase is separated off, driedover sodium sulfate and evaporated. The residue is chromatographed on asilica gel column with dichloromethane/methanol as eluent:6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-ylmethyl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“A14”) as colourless crystals; ESI 489;

¹H-NMR (CDCl₃): δ [ppm]=2.29 (s, 3H), 2.48 (m, 8H), 3.54 (s, 2H), 5.50(s, 2H), 6.86 (tt, J₁=8.8 Hz, J₂=2.3 Hz, 1H), 7.04 (d, J =9.5 Hz, 1H),7.34 (m, 2H), 7.47 (t, J=7.8 Hz, 1H), 7.58 (d, J=9.5 Hz, 1H), 7.58 (m,1H), 8.38 (dt, J₁=7.8 Hz, J₂=1 Hz, 1H), 8.64 (t, J=1 Hz, 1H), 8.74 (s,2H).

The following compound is obtained analogously

-   -   6-(3,5-difluorophenyl)-2-[3-(5-dimethylaminomethylpyrimidin-2-yl)-benzyl]-2H-pyridazin-3-one

EXAMPLE 8

The preparation of3-{1-[3-(5-methylpyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile(“A15”) is carried out analogously to the following scheme

8.1 1.31 ml (11.0 mmol) of 3-ethoxymethacrolein and 2.04 ml (11.0 mmol)of a 30% solution of sodium ethoxide in methanol are added to asuspension of 2.41 g (10.0 mmol) of methyl 3-carbamimidoylbenzoateacetate (preparation see Example 37) in 40 ml of methanol, and theresultant solution is stirred at 50° C. for 18 hours. The reactionmixture is evaporated in vacuo, and water is added. The resultantprecipitate is filtered off with suction, washed with water and dried invacuo: methyl 3-(5-methylpyrimidin-2-yl)benzoate as colourless crystals;ESI 229.

8.2 600 mg (5.41 mmol) of powdered calcium chloride are added to asuspension of 400 mg (10.6 mmol) of sodium borohydride in 20 ml of THF,and the mixture is stirred at room temperature for 1.5 hours. A solutionof 751 mg (3.29 mmol) of methyl 3-(5-methylpyrimidin-2-yl)benzoate in 10ml of THF is added dropwise to this suspension with stirring, and themixture is stirred at room temperature for 18 hours. 10 ml of 1 N NaOH,water and dichloromethane are added to the reaction mixture, which isthen filtered. The organic phase of the filtrate is separated off, driedover sodium sulfate and evaporated. The residue is chromatographed on asilica gel column with dichloromethane/methanol as eluent:[3-(5-methylpyrimidin-2-yl)-phenyl]methanol as colourless solid; ESI201.

8.3 147 μl (0.75 mmol) of diisopropyl diazodicarboxylate are addeddropwise to a suspension of 98.6 mg (0.50 mmol) of3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 100 mg (0.50 mmol) of[3-(5-methylpyrimidin-2-yl)phenyl]methanol and 197 mg (0.75 mmol) oftriphenylphosphine in 3 ml of THF, and the resultant solution is stirredat room temperature for 18 hours. The reaction mixture is evaporated invacuo, and 2-propanol is added to the residue. The resultant precipitateis filtered off with suction and chromatographed on a silica gel columnwith dichloromethane/methanol as eluent:3-{1-[3-(5-methylpyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile(“A15”) as yellowish solid; ESI 380; ¹H NMR (DMSO-d₆): δ [ppm]=2.31 (s,3H), 5.46 (s, 2H), 7.16 (d, J=9.7 Hz, 1H), 7.51 (m, 2H), 7.72 (t, J=8.0Hz, 1H), 7.93 (dt, J₁=7.5 Hz, J₂=1 Hz, 1H), 8.17 (d, J=9.7 Hz, 1H), 8.25(dt, J₁=7.8 Hz, J₂=1 Hz, 1H), 8.30 (dt, J₁=6.8 Hz, J₂=1.6 Hz, 1H), 8.37(t, J=1.6 Hz, 1H), 8.46 (bs, 1H), 8.75 (s, 2H).

The following compounds are obtained analogously

-   -   6-benzo-1,2,5-thiadiazol-5-yl-2-[3-(5-methylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one,        ESI 413,

EXAMPLE 9

The preparation ofN′-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}-pyrimidin-5-yl)-N,N-dimethylformamidine(“A16”),2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one(“A17”) and

-   6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one    (“A18”) is carried out analogously to the following scheme

9.1 A sodium methoxide solution prepared by dissolution of 3.45 g (150mmol) of sodium in 35 ml of methanol is added dropwise to a suspension,kept under nitrogen, of 20.0 g (50.0 mmol) of3-[6-oxo-3-(3,5-difluorophenyl)-6H-pyridazin-1-ylmethyl]benzamidiniumacetate and 24.4 g (50.0 mmol) of({2-dimethylamino-1-[dimethylimmoniomethyl]vinylamino}-methylene)dimethylammoniumdihexafluorophosphate in 20 ml of methanol. The reaction mixture isslowly warmed to 60° C. and stirred at this temperature for 20 minutes.The reaction mixture is cooled to room temperature and partitionedbetween water and dichloromethane. The organic phase is dried oversodium sulfate and evaporated. The residue is taken up in methanol,filtered off with suction, the residue is washed with ether and dried invacuo:N′-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}pyrimidin-5-yl)-N,N-dimethylformamidine(“A16”) as colourless crystals; ESI 447.

9.2 190 ml of dioxane and 17.4 g (39.0 mmol) ofN′-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)-N,N-dimethylformamidineare added to a solution of 19.1 g (137 mmol) of potassium carbonate in380 ml of water. The reaction mixture is heated at the boil for 3 daysand subsequently cooled to room temperature. The resultant precipitateis filtered off with suction, washed with water and dried in vacuo:2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one(“A17”) as colourless crystals; ESI 392.

9.3 501 mg (2.55 mmol) of bis(2-chloroethyl)methylammonium chloride areadded to a solution, kept under nitrogen, of 587 mg (1.5 mmol) of2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-onein 2 ml of 1-methylpyrrolidone, and the reaction mixture is heated at130° C. for 32 hours. The reaction mixture is cooled, dichloromethane isadded, and the mixture is filtered. The filtrate is evaporated in vacuo,and the residue is chromatographed on a silica gel column withdichloromethane/methanol. The product-containing fractions are combinedand evaporated, and the residue is recrystallised from methanol. Thismaterial is suspended in methanol and converted into the hydrochlorideusing hydrogen chloride in diethyl ether, and the hydrochloride isprecipitated using diethyl ether:6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“A18”) hydrochloride as colourless crystals; ESI 475;

¹H-NMR (DMSO-d₆): δ [ppm]=2.81 (d, J=3.3 Hz, 3H), 3.19 (m 2H), 3.30 (m,2H), 3.50 (m, 2H), 4.05 (m, 2H), 5.43 (s, 2H), 7.14 (d, J=9.5 Hz, 1H),7.35 (tt, J₁=8.8 Hz, J₂=2.3 Hz, 1H), 7.47 (m, 2H), 7.66 (m, 2H), 8.15(d, J=9.5 Hz, 1H), 8.22 (m, 1H) 8.34 (bs,1H), 8.65 (s, 2H), 11.0 (bs,1H).

The following compounds are obtained analogously

-   -   6-(3,5-difluorophenyl)-2-[3-(5-piperazin-1-ylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one        (“A19”) hydrochloride, ESI 461,

¹H-NMR (d₆-DMSO): δ [ppm]=3.25 (m, 4H), 3.59 (m, 4H), 5.44 (s, 2H), 7.16(d, J=10 Hz, 1H), 7.37 (tt, J₁=9.2 Hz, J₂=2 Hz, 1H), 7.47 (m, 2H), 7.67(m, 2H), 8.16 (d, J=10 Hz, 1H), 8.22 (m, 1H), 8.35 (bs, 1H), 8.65 (s,2H), 9.38 (bs, 2H);

-   -   2-{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one        (“A20”), hydrochloride, ESI 493;    -   2-{3-[5-(piperazin-1-yl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one        (“A65”);    -   N′-(2-{3-[3-(3,4,5-trifluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yl)-N,N-dimethylformamidine        (“A76”), ESI 465;    -   2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one        (“A82”), ESI 410.

EXAMPLE 10

The preparation of6-(3,5-difluorophenyl)-2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-2H-pyridazin-3-one(“A21”) and6-(3,5-difluorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“A22”) is carried out analogously to the following scheme

10.1 A suspension of 4.76 g (12.2 mmol) of2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-onein a mixture of 5.40 ml of concentrated sulfuric acid and 44 ml of wateris heated at the boil for 4 hours. The reaction mixture is cooled toroom temperature, diluted with ice-cold water and rendered alkalineusing conc. aqueous ammonia. The precipitate is filtered off withsuction, washed with water and dried. The crude product isrecrystallised from methanol:6-(3,5-difluorophenyl)-2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-2H-pyridazin-3-one(“A21”) as colourless crystals; ESI 393.

10.2 98.3 μl (0.82 mmol) of 3-(dimethylamino)-1-propanol, 218 mg (0.82mmol) of triphenylphosphine are added to a suspension, kept undernitrogen, of 215 mg (0.55 mmol) of6-(3,5-difluorophenyl)-2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-2H-pyridazin-3-onein 5 ml of THF, and the mixture is cooled in an ice bath. 170 μl (0.82mmol) of diisopropyl azodicarboxylate are added dropwise, and thereaction mixture is stirred at room temperature for 2 hours. Thereaction mixture is evaporated in vacuo, and the residue ischromatographed on a silica gel column with dichloromethane/methanol aseluent. The product-containing fractions are combined and evaporated.This material is dissolved in acetone and converted into thehydrochloride using hydrogen chloride in diethyl ether, and thehydrochloride is precipitated using diethyl ether:6-(3,5-difluorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“A22”) hydrochloride as colourless crystals; ESI 478;

¹H-NMR (DMSO-d₆): δ [ppm]=2.21 (m, 2H), 2.78 (d, J=5 Hz, 6H), 3.22 (m2H), 4.31 (t, J=6 Hz, 2H), 5.44 (s, 2H), 7.14 (d, J=9.5 Hz, 1H), 7.35(tt, J₁=8.8 Hz, J₂=2.3 Hz, 1H), 7.49 (m, 2H), 7.66 (m, 2H), 8.15 (d,J=9.5 Hz, 1H), 8.24 (m, 1H) 8.38 (bs, 1H), 8.65 (s, 2H), 10.7 (bs, 1H).

The following compound are obtained analogously

-   -   6-(3,5-difluorophenyl)-2-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

hydrochloride, ESI 490;

-   -   6-(3,5-difluorophenyl)-2-{3-[5-(3-pyrrolidin-1-ylpropoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one

-   -   6-(3,5-difluorophenyl)-2-(3-{5-[2-(4-methylpiperazin-1-yl)ethoxy]-pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one,        hydrochloride,

-   -   -   2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one

-   -   2-{3-[5-(2-dimethylaminoethoxy)pyrimidin-2-yl]benzyl}-6-(3,5-difluorophenyl)-2H-pyridazin-3-one        (“A64”) hydrochloride, ESI 464;    -   6-(3,5-difluorophenyl)-2-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one,        ESI 504,

hydrochloride, ESI 450 (precursor BOC-protected compound);

-   6-(3,5-difluorophenyl)-2-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one    hydrochloride, ESI 476

(precursor BOC-protected compound),

¹H-NMR spectrum of “A102” hydrochloride:

¹H-NMR (d₆-DMSO): δ [ppm]=1.94 (m, 2H), 2.19 (m, 2H), 3.08 (m, 2H), 3.26(m, 2H), 4.89 (m, 1H), 5.44 (s, 2H), 7.15 (d, J=10 Hz, 1H), 7.36 (tt,J₁=9.2 Hz, J₂=2 Hz, 1H), 7.50 (m, 2H), 7.66 (m, 2H), 8.16 (d, J=10 Hz,1H), 8.24 (m, 1H), 8.37 (bs, 1H), 8.71 (s, 2H), 9.11 (bs, 1H), 9.19 (bs,1H).

EXAMPLE 11

The preparation of6-(3,5-difluorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)pyridin-2-yl]benzyl}-2H-pyridazin-3-one(“A24”), ESI 477, is carried out analogously to the following scheme

EXAMPLE 12

The preparation of2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one(“A25”) and6-(3,5-difluorophenyl)-2-{3-[5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“A26”) is carried out analogously to the following scheme

12.1 750 mg (0.65 mmol) of tetrakis(triphenylphosphine)palladium areadded to a solution, kept under nitrogen, of 6.11 g (21.5 mmol) of5-bromo-2-iodopyrimidine, 3.91 g (25.7 mmol) of3-(hydroxymethyl)benzeneboronic acid and 9.11 g (42.9 mmol) oftripotassium phosphate trihydrate in 120 ml of dioxane and 14 ml ofwater, and the mixture is stirred at 90° C. for 18 hours. The reactionmixture is cooled to room temperature, tert-butyl methyl ether and waterare added, and the mixture is filtered through kieselguhr. The organicphase of the filtrate is separated off, dried over sodium sulfate andevaporated. The residue is chromatographed on a silica gel column withdichloromethane/methanol as eluent:[3-(5-bromopyrimidin-2-yl)phenyl]methanol as pale-yellow crystals; ESI265,267.

12.2 2.60 ml (13.2 mmol) of diisopropyl azodicarboxylate are addeddropwise to a suspension of 2.76 g (13.2 mmol) of6-(3,5-difluorophenyl)-2H-pyridazin-3-one, 2.49 g (8.83 mmol) of[3-(5-bromopyrimidin-2-yl)-phenyl]methanol, and 3.47 g (13.2 mmol) oftriphenylphosphine in 30 ml of THF, and the reaction mixture is stirredat room temperature for 18 hours. The reaction mixture is evaporated invacuo, taken up in 2-propanol, heated to the boil and allowed to cool.The resultant precipitate is filtered off with suction, washed with2-propanol and re-recrystallised from 2-propanol:2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one(“A25”) as colourless crystals; ESI 455,457;

¹H-NMR (DMSO-d₆): δ [ppm]=5.45 (s, 2H), 7.14 (d, J=9.5 Hz, 1H), 7.35(tt, J₁=8.8 Hz, J₂=2.3 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.59 (m, 1H),7.66 (m, 2H), 8.14 (d, J=9.5 Hz, 1H), 8.29 (m, 1H), 8.38 (bs, 1H), 9.06(s, 2H).

12.3 425 mg (2.0 mmol) of tripotassium phosphate trihydrate and 56.2 mg(0.08 mmol) of bis(triphenylphosphine)palladium chloride are added to asolution, kept under nitrogen, of 455 mg (1.00 mmol) of2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-oneand 229 mg (1.10 mmol) of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in10 ml of 1,2-dimethoxyethane, and the mixture is stirred at 80° C. for18 hours, during which a grey precipitate forms. The reaction mixture isdiluted with water and filtered. The residue is chromatographed on asilica gel column with dichloromethane/methanol as eluent:6-(3,5-difluorophenyl)-2-{3-[5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one(“A26”) as colourless crystals; ESI 457;

¹H-NMR (DMSO-d₆): δ [ppm]=3.80 (s, 3H), 5.44 (s, 2H), 7.13 (d, J=9.5 Hz,1H), 7.29 (tt, J₁=8.8 Hz, J₂=2.3 Hz, 1H), 7.50 (m, 2H), 7.64 (m, 2H),8.05 (s, 1H), 8.14 (d, J=9.5 Hz, 1H), 8.32 (m, 1H), 8.35 (s, 1H), 8.45(bs,1H), 9.11 (s, 2H).

The following compounds are obtained analogously:

“A63”: ¹H-NMR (DMSO-d₆): δ [ppm]=1.81 (m, 2H), 2.01 (m, 2H), 2.15 (bs,1H), 2.61 (m, 2H), 3.06 (m, 2H), 4.24 (m, 1H), 5.47 (s, 2H), 7.16 (d,J=9.5 Hz, 1H), 7.36 (tt, J₁=8.8 Hz, J₂=2.3 Hz, 1H), 7.53 (m, 2H), 7.68(m, 2H), 8.10 (s, 1H), 8.16 (d, J=9.5 Hz, 1H), 8.33 (m, 1H), 8.46(bs,1H), 8.48 (s, 1H), 9.14 (s, 2H);

HPLC (Rt in Compound ESI min) No. Name and/or structure [M + H]⁺ method“A103”

“A104”

“A105”

“A106”

“A107”

“A108”

“A109”

EXAMPLE 13

The preparation of6-(3,5-difluorophenyl)-2-{3-[6-(4-methylpiperazin-1-yl)-pyridazin-3-yl]benzyl}-2H-pyridazin-3-one(“A27”) and6-(3,5-difluorophenyl)-2-{3-[6-(3-dimethylaminopropoxy)pyridazin-3-yl]benzyl}-2H-pyridazin-3-one(“A28”) is carried out analogously to the following scheme

The following compounds are obtained analogously

-   -   6-(3,5-difluorophenyl)-2-{3-[6-(3-dimethylaminopropylamino)pyridazin-3-yl]benzyl}pyridazin-3-one        (“A67”) hydrochloride, ESI 477,

-   -   6-(3,5-difluorophenyl)-2-{3-[6-(2-dimethylaminoethylamino)pyridazin-3-yl]benzyl}pyridazin-3-one        (“A68”) hydrochloride, ESI 463;    -   6-(3,5-difluorophenyl)-2-{3-[6-(4-dimethylaminobutylamino)pyridazin-3-yl]benzyl}pyridazin-3-one        (“A69”);    -   6-(3,5-difluorophenyl)-2-{3-[6-(1-methylpiperidin-4-ylamino)pyridazin-3-yl]benzyl}pyridazin-3-one

EXAMPLE 14

The preparation of ethyl2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carboxylate(“A29”) is carried out analogously to the following scheme

4.7 g (11.23 mmol) of3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]benzamidiniumacetate are suspended in 40 ml of pyridine, and 2.4 g (16.85 mmol) ofethyl 2-formyl-3-oxopropionate (prepared in accordance with S. H. Berzet al., Journal of Organic Chemistry 1982, 47, 2216) are added, and themixture is stirred at 80° C. for 4 h. A further 500 mg (3.47 mmol) ofethyl 2-formyl-3-oxopropionate are subsequently added, and the mixtureis stirred at 80° C. for 1 h. The reaction mixture is stirred into 400ml of water, and the precipitate is filtered off with suction, washed anumber of times with water and dried in a drying cabinet.

Yield: 4.43 g of “A29” (76%), Rt=3.58 min (method B), ESI 467.

The following compounds are obtained analogously

-   -   ethyl        2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidine-5-carboxylate

Preparation of6-(3,5-difluorophenyl)-2-[3-(5-hydroxymethylpyrimidin-2-yl)-benzyl]-2H-pyridazin-3-one(“A101”)

1 g (2.43 mmol) of2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}pyrimidine-5-carbaldehyde[preparation Example 7] is suspended in 15 mol of ethanol and 15 ml ofTHF. The reaction mixture is cooled to 5° C., 374 mg (9.89 mmol) ofsodium borohydride are added, and the mixture is brought to roomtemperature over the course of 30 min. The reaction mixture is pouredinto a mixture of ice/water/1 N HCl (1:1:1). The precipitated product isfiltered off with suction and dried in a drying cabinet.

Yield: 960 mg, white solid “A101”, ESI 407.

EXAMPLE 15

The preparation of2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-yl-methyl]phenyl}pyrimidine-5-carboxylicacid (“A31”) is carried out analogously to the following scheme

3.4 g (7.29 mmol) of ethyl2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carboxylateare dissolved in 300 ml of THF and 30 ml of water, and 713 mg (29.2mmol) of lithium hydroxide are added. The reaction mixture is refluxedfor 4 h and cooled to room temperature, and the organic solvent isremoved by distillation in a rotary evaporator. 300 ml of water and 30ml of THF are added to the residue, and conc. HCl is slowly addeddropwise to this solution with stirring until the reaction is stronglyacidic. The precipitate formed is filtered off with suction, washed withcopious water and dried in a vacuum drying cabinet.

Yield: 2.87 g of “A31”, Rt=3.06 min (method B), ESI 439.

The following compound is obtained analogously

-   -   2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}-pyrimidine-5-carboxylic        acid (“A32”), ESI 421.

EXAMPLE 16

The preparation ofN-(2-dimethylaminoethyl)-2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carboxamide(“A33”) is carried out analogously to the following scheme

150 mg (0.334 mmol) of2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carboxylicacid are dissolved in 2 ml of DMF, and 75 μl (0.67 mmol) of4-methylmorpholine, 97 mg (0.50 mmol) of EDCl and 60 mg (0.43 mmol) ofHOBt are added. 47 μl (0.43 mmol) of N,N-dimethylaminoethylenediamineare added, and the reaction mixture is stirred at room temperature for18 h. The reaction solution is separated directly by means ofpreparative HPLC.

Yield: 124 mg of “A33” trifluoroacetate; Rt=2.63 (method B); ESI 509.

The following compounds are obtained analogously

HPLC (Rt in Compound ESI min) No. Name and/or structure [M + H]⁺ method“A34”

523 2.64 B “A35”

537 2.66 B “A36”

581 3.28 B “A37”

595 3.34 B “A38”

609 3.36 B “A39”

438 2.90 B “A40”

562 2.72 B “A41”

521 2.63 B “A42”

510 2.91 B “A43”

621 3.48 B “A44”

657 (M + Na) 3.51 B “A44a” from “A44” using TFA/dioxane:

535 “A45”

549 2.68 B “A46”

549 2.68 B “A47”

565 2.65 B “A48”

578 2.50 B “A49”

519 2.60 B “A50”

544 2.64 B “A71”

509 “A72”

495 “A73”

509 “A74”

481 “A84”

521 “A90”

537 “A92”

509

EXAMPLE 17

The preparation ofN-[2-(1H-imidazol-4-yl)ethyl]-2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carboxamide(“A51”) is carried out analogously to the following scheme

150 mg (0.334 mmol) of2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carboxylicacid are dissolved in 2 ml of DMF, and 75 μl (0.67 mmol) of4-methylmorpholine, 97 mg (0.50 mmol) of EDCl and 60 mg (0.43 mmol) ofHOBt are added. 51 mg (0.44 mmol) of histamine are added, and thereaction mixture is stirred at room temperature for 18 h. Water is addedto the reaction mixture, and the resultant precipitate is filtered offwith suction. Acetonitrile is added to the residue, which is againfiltered off with suction, and the residue is dried in vacuo.

Yield: 127 mg of “A51”, Rt=2.63 min (method B), ESI 532.

The following compounds are obtained analogously

HPLC (Rt in Compound ESI min) No. Name and/or structure [M + H]⁺ method“A52”

547 2.85 B “A53”

563 2.99 B

EXAMPLE 18

The preparation of2-[3-(5-chloropyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one(“A54”) is carried out analogously to the following scheme

250 mg (0.60 mmol) of3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]benzamidiniumacetate are suspended in 3 ml of pyridine, 74 mg (0.66 mmol) of2-chloromalonaldehyde are added, and the mixture is stirred at 90° C.for 15 h. The reaction mixture is evaporated, and the residue ispurified by means of preparative HPLC, giving “A54”.

EXAMPLE 19

The preparation of2-[3-(4-methylpyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one(“A3”) is carried out analogously to the following scheme

150 mg (0.36 mmol) of3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]benzamidiniumacetate and 99.5 mg (0.72 mmol) of potassium carbonate are suspended in5 ml of acetonitrile, 42 mg (0.3 mmol) of4-trimethylsilyl)-3-butyn-2-one are added, and the mixture is heated ina microwave reactor at 120° C. for 45 min (Emrys optimiser). Thereaction mixture is filtered and evaporated, and the residue is purifiedby means of preparative HPLC.

Yield: 16 mg of “A3”, white solid, Rt=3.38 min (method B), ESI-MS: 408.

EXAMPLE 20

The preparation of2-(3-pyrimidin-2-ylbenzyl)-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one(“A4”) is carried out analogously to the following scheme

150 mg (0.36 mmol) of3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]benzamidiniumacetate and 1.1 ml (6.6 mmol) of 1,1,3,3-tetramethoxypropane are stirredat 175° C. for 1 h. The reaction mixture is purified directly by meansof preparative HPLC.

Yield: 23 mg of “A4”, white solid; Rt=3.28 min (method B); ESI-MS: 395.

EXAMPLE 21

The preparation of4-{1-[3-(5-methylpyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}-N-(3-piperidin-1-ylpropyl)benzamide(“A55”) is carried out analogously to the following scheme

1.5 g (6.94 mmol) of 4-(6-oxo-1,6-dihydropyridazin-3-yl)benzoic acid(preparation according to DE 10010422) are dissolved in 20 ml of DMF,1.18 g (8.33 mmol) of 3-piperidinopropylamine, 1.56 ml (13.9 mmol) of4-methylmorpholine, 2.7 g (13.9 mmol) of EDCl and 967 mg (6.94 mmol) ofHOBt are added, and the mixture is stirred at room temperature for 18 h.The DMF is removed by distillation, and 2 M NaOH is added to theresidue. The mixture is evaporated, and 100 ml of THF are added, themixture is stirred for 1 h and filtered, 50 ml of ether are added, and10 ml of 4 N HCl in dioxane are added. An oil forms in the process, thesupernatant is decanted off, ether is again added, and the supernatantis decanted again. 30 ml of isopropanol are added to the oily residue.After 3 days, crystals form, which are filtered off with suction, washedwith isopropanol and dried.

Yield: 500 mg of “A55”, Rt=1.70 min, ESI 341.

EXAMPLE 22

The preparation ofN-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)-2-dimethylaminoacetamide(“A85”) is carried out analogously to the following scheme

trifluoroacetate, ESI 477.

The following compounds are obtained analogously

-   -   N-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yl)-4-dimethylaminobutyramide        hydrochloride

-   -   N-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yl)-3-dimethylaminopropionamide

EXAMPLE 23

Reaction of

with Cl—CO—CH₂—N(CH₃)COO-tert-butyl under standard conditions andconventional work-up gives

The following compound is obtained analogously

EXAMPLE 24

The preparation of2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carbonitrile(“A77”) and of2-[3-(5-aminomethylpyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one(“A93”) is carried out analogously to the following scheme

24.1 3.5 g (18.6 mmol) of3-dimethylamino-2-cyano-2-propen-1-yl-idene)dimethylammonium chloride(prepared analogously to U.S. Pat. No. 3,853,946) are suspended in 60 mlof pyridine, and 7.8 g (18.6 mmol) of3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]benzamidiniumacetate are added. The suspension is stirred at 100° C. for 4 hours.After cooling to room temperature, the mixture is stirred into 300 ml ofwater, and the crystals are filtered off with suction and washed withwater. The solid is dried in a vacuum drying cabinet;

Yield: 6.14 g of “A77”, beige crystals;

HPLC: Rt=3.34 min (method C); LC-MS: 420 (M+H).

24.2 2.9 g (6.9 mmol) of2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carbonitrile(“A77”) are dissolved in 60 ml of THF and 60 ml of methanol, and 2 g ofRaney nickel are added. The mixture is subsequently hydrogenated atatmospheric pressure under a hydrogen atmosphere for 6 h. The catalystis filtered off with suction and washed with THF, and the filtrate isevaporated.

Yield: 2.9 g of “A93”, pale-yellow solid; HPLC: 2.53 min (method C);

LC-MS: 424 (M+H).

EXAMPLE 25

The preparation of6-(3,5-difluorophenyl)-2-[3-(6-oxo-1,6-dihydropyrimidin-2-yl)benzyl]-2H-pyridazin-3-one(“A80”), ESI 393, and of6-(3,5-difluorophenyl)-2-{3-[4-(3-dimethylaminopropoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one(“A81”) hydrochloride, ESI 478, is carried out analogously to thefollowing scheme

EXAMPLE 26

The preparation of2-(3-pyrimidin-5-ylbenzyl)-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one(“A83”), ESI 395, is carried out analogously to the following scheme

The following compounds are obtained analogously

-   -   2-[3-(6-methylpyridin-3-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one        (“A86”), ESI 408;    -   2-(3-pyridin-4-ylbenzyl)-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one        (“A94”), ESI 394;

The synthesis of “A83”, “A86” and “A94” can also be carried outanalogously to Example 4.

EXAMPLE 26a

The preparation of2-[3-(5-methylpyrimidin-2-yl)benzyl]-6-(2H-pyrazol-3-yl)-2H-pyridazin-3-one(“A100”), ESI 345 is carried out analogously to Example 8.

EXAMPLE 27

The preparation of3-(4-methylpiperazin-1-yl)-N-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-ylmethyl)-propionamide(“A96”), ESI 578, is carried out analogously to the following scheme

169 mg (0.4 mmol) of2-[3-(5-aminomethylpyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-oneand 83 mg (0.48 mmol) of 3-(4-methylpiperazin-1-yl)propanoic acid aresuspended in 2 ml of DMF, and 90 μl (0.8 mmol) of N-methylmorpholine,116 mg (0.60 mmol) of EDCl and 72 mg (0.52 mmol) of HOBt are added, andthe mixture is stirred at room temperature for 15 h. 10 ml of water areadded to the reaction mixture, which is then extracted with ethylacetate. The crude product is crystallised using ether.

Yield: 104 mg of “A96”, beige solid; HPLC: Rt=2.49 min

LC-MS: 578 (M+H).

The following compounds are obtained analogously

-   -   2-(4-methylpiperazin-1-yl)-N-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-ylmethyl)acetamide,        ESI 564,

-   -   2-methylamino-N-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-ylmethyl)acetamide,        trifluoroacetate, ESI 495

-   -   3-dimethylamino-N-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-ylmethyl)propionamide        (“A99”) trifluoroacetate, ESI 523,

EXAMPLE 28

The preparation of4-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}-pyrimidin-5-yl)morpholin-3-one(“A75”) is carried out analogously to the following scheme

EXAMPLE 29

The preparation of6-[4-(3-dimethylaminopropoxy)-3,5-difluorophenyl]-2-[3-(5-methylpyrimidin-2yl)benzyl]-2H-pyridazin-3-one(“A78”) trifluoroacetate, ESI 492, is carried out analogously to thefollowing scheme

63 μl (0.54 mmol) of 3-dimethylaminopropan-1-ol is dissolved in 10 ml ofDMF, and 22 mg (0.54 mmol) of sodium hydride in paraffin oil (60%) areadded, and the mixture is stirred for 15 min. 200 mg (0.49 mmol) of2-[3-(5-methylpyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-oneare subsequently added. After 2 h at room temperature, the reaction isterminated by addition of 2 ml of 1 N HCl. The solution is evaporatedand purified by means of preparative HPLC.

Yield: 9 mg of “A78”, Rt=2.51 min (method C), LC-MS: 492 (M+H).

EXAMPLE 30

The following compounds are obtained analogously to Example 8

HPLC (Rt in Compound ESI min) No. Name and/or structure [M + H]⁺ method“A112”

412 “A113”

359

EXAMPLE 31

The following compounds are obtained analogously to Example 10

HPLC (Rt in Compound ESI min) No. Name and/or structure [M + H]⁺ method“A114”

504 “A115”

504 “A116”

504 “A117”

451 “A118”

476 “A119” 6-(3,5-difluorophenyl)-2-{3-[5-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)pyrimidin-2-yl]benzyl}-2H- pyridazin-3-one,trifluoroacetate

516 “A120”

533 “A121” 6-(3,5-difluorophenyl)-2-{3-[5-((S)-1-methylpyrrolidin-3-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, trifluoroacetate

476 “A122” 6-(3,5-difluorophenyl)-2-{3-[5-((R)-1-methylpyrrolidin- 4763-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, trifluoroacetate“A123”

432 “A124”

443 “A125”

472 “A126”

505 “A127” 6-(3,5-difluorophenyl)-2-{3-[5-(2-pyrrolidin-1-yl- 490ethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, hydrochloride “A128”6-(3,5-difluorophenyl)-2-{3-[5-(3-morpholin-4-yl- 520propoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, trifluoroacetate“A129”

506 “A130” 6-(3,5-difluorophenyl)-2-{3-[5-(2-morpholin-4-yl- 506ethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, hydrochloride “A131”

490

EXAMPLE 32

The following compounds are obtained analogously to Example 10 withsubsequent removal of Boc

HPLC (Rt in Compound ESI min) No. Name and/or structure [M + H]⁺ method“A132” 6-(3,5-difluorophenyl)-2-{3-[5-(4-methylamino- 478butoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, hydrochloride “A133”6-(3,5-difluorophenyl)-2-{3-[5-(3-methylamino- 464propoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3- one, hydrochloride “A134”6-(3,5-difluorophenyl)-2-{3-[5-(pyrrolidin-3-yl- 476methoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3- one, hydrochloride “A135”6-(3,5-difluorophenyl)-2-{3-[5-(3-ethylamino- 478propoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3- one, hydrochloride “A136”2-{3-[5-(2-aminoethoxy)pyrimidin-2-yl]benzyl}-6- 436(3,5-difluorophenyl)-2H-pyridazin-3-one, hydro- chloride “A137”6-(3,5-difluorophenyl)-2-{3-[5-(piperidin-3-yloxy)- 476pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, hydro- chloride “A138”6-(3,5-difluorophenyl)-2-{3-[5-(piperidin-4-yl- 490methoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3- one, hydrochloride “A139”6-(3,5-difluorophenyl)-2-{3-[5-(pyrrolidin-3-yloxy)- 462pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, trifluoroacetate “A140”6-(3,5-difluorophenyl)-2-{3-[5-((S)-pyrrolidin-3- 462yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, trifluoroacetate “A141”6-(3,5-difluorophenyl)-2-{3-[5-((R)-pyrrolidin-3- 462yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, trifluoroacetate “A142”2-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-pyridin-4-yl-2H-pyridazin-3-one

441 “A143” 4-(6-oxo-1-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]-benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile

465 “A144” 3-(6-oxo-1-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]- 465benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile “A145”6-(3,5-difluorophenyl)-2-{3-[5-(2-piperazin-1-yl- 505ethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, trifluoroacetate“A146” 6-(3,5-difluorophenyl)-2-{3-[5-(piperidin-4-yloxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A147”3-(6-oxo-1-{3-[5-(2-piperazin-1-ylethoxy)- 494pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)- benzonitrile “A148”6-(3-fluorophenyl)-2-{3-[5-(piperidin-4-yl- 472methoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3- one

EXAMPLE 33

The following compounds are obtained analogously to Example 12 withsubsequent removal of Boc

Compound ESI No. Name and/or structure [M + H]⁺ “A149”2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]-benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one

544 “A150” 3-(6-oxo-1-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl) benzonitrile

515 “A151” 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3- one,trifluoroacetate

494 “A152” 6-(3-methoxyphenyl)-2-{3-[5-(1-piperidin-4-yl-1H- 520pyrazol-4-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3- one,trifluoroacetate “A153”6-(3-fluorophenyl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4- 508yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A154”6-(3,5-difluorophenyl)-2-{3-[5-(1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

443 “A155” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-methylaminoethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3- one,hydrochloride

500 “A156” 6-(3-chlorophenyl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, hydro- chloride

524 “A157”

hydrochloride 508 “A158”6-(3,5-difluorophenyl)-2-(3-{5-[1-(3-methylaminopropyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3- one,hydrochloride 514 “A159”3-[1-(3-{5-[1-(2-methylaminoethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]- benzonitrile

489 ¹H-NMR (d₆-DMSO): δ [ppm] = 2.1 (bs, 1H), 2.35 (s, 3H), 2.97 (t, J =6.2 Hz, 2H), 4.28 (t, J = 6.2 Hz, 2H), 5.53 (s, 2H), 7.23 (d, J = 9.8Hz, 1H), 7.58 (m, 2 Hz, 2H), 7.79 (t, J = 8.0 Hz, 1H), 8.00 (dt, J₁ =7.5 Hz, J₂ =1.2 Hz, 1H), 8.16 (s, 1H), 8.25 (d, J = 9.8 Hz, 1H), 8.32(dt, J₁ = 7.5 Hz, J₂ = 1.2 Hz, 1H), 8.38 (dt, J₁ =6.5 Hz, J₂ = 1.8 Hz,1H), 8.45 (t, J = 1.6 Hz, 1H), 8.46 (s, 1H), 8.53 (bs, 1H), 9.20 (s, 2H)“A160” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3- one

555 “A161” 3-(6-oxo-1-{3-[5-(1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile

432 ¹H-NMR (d₆-DMSO): δ [ppm] = 5.48 (s, 2H), 7.18 (d, J = 10 Hz, 1H),7.53 (t, J = 7.5 Hz, 1H), 7.55 (m, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.94(dt, J₁ = 7.5 Hz, J₂ = 1.2 Hz, 1H), 8.15 (bs, 1H), 8.19 (d, J = 10 Hz,1H), 8.27 (dt, J₁ = 7.5 Hz, J₂ = 1.2 Hz, 1H), 8.33 (dt, J₁ = 6.5 Hz, J₂= 1.8 Hz, 1H), 8.39 (t, J = 1.6 Hz, 1H), 8.44 (bs, 1H), 8.48 (bs, 1H),9.18 (s, 2H), 13.2 (bs, 1H) “A162”3-[6-oxo-1-(3-{5-[1-(2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-1,6-dihydropyridazin-3-yl]- benzonitrile

544

EXAMPLE 34

The following compounds are obtained analogously to Example 16

HPLC (Rt in Compound ESI min) No. Name and/or structure [M + H]⁺ method“A163” N-(4-dimethylaminobutyl)-2-[3-(6-oxo-3-pyridin-4-yl-6H-pyridazin-1-ylmethyl)phenyl]pyrimidine-5- carboxamide,trifluoroacetate

484 “A164” N-(4-dimethylaminobutyl)-2-{3-[3-(4-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5- carboxamide,trifluoroacetate

508

EXAMPLE 35

The following compounds are obtained analogously to Example 27

Compound No. Name and/or structure ESI [M + H]⁺ HPLC (Rt in min) methodB “A165”

595 3.18 Compound “A98” is obtained therefrom by removal of Boc. “A166”

509 2.59 “A167”

631 (M + Na) 3.22 Compound “A168”, trifluoroacetate, ESI 509, isobtained therefrom by removal of Boc

EXAMPLE 36

The preparation of the compound3-[6-oxo-1-(3-{5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-1,6-dihydropyridazin-3-yl]-benzonitrile(“A168”) is carried out analogously to the following scheme

36.1 A solution of 70.0 g (660 mmol) of sodium carbonate in 325 ml ofwater is added to a solution, kept under nitrogen, of 95.0 g (332 mmol)of 5-bromo-2-iodopyrimidine in 325 ml of toluene, and the mixture isheated to 80° C. 2.3 g (3.3 mmol) ofbis(triphenylphosphine)palladium(II) chloride are added, and a solutionof 50.0 g (329 mmol) of 3-(hydroxymethyl)-benzeneboronic acid in 650 mlof ethanol is subsequently added dropwise. The reaction mixture isstirred at 80° C. for 18 hours. The reaction mixture is cooled to roomtemperature and filtered. 1 l of ethyl acetate and 1 l of water areadded to the filtrate. The organic phase is separated off, dried oversodium sulfate and evaporated. The residue is recrystallised from2-propanol: [3-(5-bromopyrimidin-2-yl)phenyl]methanol as pale-yellowcrystals; ESI 265,267.

36.2 116 g (438 mmol) of [3-(5-bromopyrimidin-2-yl)phenyl]methanol isadded in portions with stirring to 159 ml (2.19 mol) of thionyl chlorideheld at 30° C. The reaction solution is stirred at room temperature for18 hours. The reaction mixture is evaporated. The residue is taken up intoluene and re-evaporated. This procedure is repeated three times. Theresidue is recrystallised from toluene:5-bromo-2-(3-chloromethylphenyl)pyrimidine as colourless crystals; m.p.148° C.; ESI 283, 285, 286.

36.3 87.9 g (310 mmol) of 5-bromo-2-(3-chloromethylphenyl)pyrimidine and111 g (341 mmol) of caesium carbonate are added to a suspension of 61.1g (310 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile in 600ml of DMF, and the mixture is stirred at 40° C. for 24 hours. Thereaction mixture is added to 600 ml of water. The resultant precipitateis filtered off with suction, washed with water and dried in vacuo:3-{1-[3-(5-bromopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrileas beige crystals, ESI 444, 446.

36.4 A solution of 10.0 g (50.5 mmol) of pyrazole-4-boronic acid pinacolester is dissolved in 100 ml of acetonitrile, and 17.5 g (101 mmol) ofN-(2-chloroethyl)pyrrolidine hydrochloride and 49.4 g (152 mmol) ofcaesium carbonate are added. The resultant suspension is stirred at roomtemperature for 18 hours. The reaction mixture is filtered with suctionand washed with acetonitrile The filtrate is evaporated and partitionedbetween ethyl acetate and saturated sodium chloride solution. Theorganic phase is dried over sodium sulfate and evaporated:1-(2-pyrrolidin-1-ylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleas pale-orange oil, which gradually crystallises;

¹H-NMR (d₆-DMSO): δ [ppm]=1.25 (s, 12H), 1.65 (m, 4H), 2.44 (m, 4H),2.79 (t, J=6.8 Hz, 2H), 4.21 (t, J=6.8 Hz, 2H), 7.56 (s, 1H), 7.93 (s,1H).

36.5 A suspension of 2.09 g (4.71 mmol) of3-{1-[3-(5-bromopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile,1.73 g (5.18 mmol) of1-(2-pyrrolidin-1-ylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(content 87%) and 2.00 g (9.42 mmol) of tripotassium phosphatetrihydrate in 20 ml of 1,2-dimethoxyethane is heated to 85° C. undernitrogen. 264 mg (0.377 mmol) of bis(triphenylphosphine)-palladium(II)chloride and 79 μl (0.57 mmol) of triethylamine are then added, and themixture is stirred at 85° C. for 18 hours. 30 ml of dichloromethane areadded to the reaction mixture, which is then filtered through kieselguhrwith suction. 100 ml of water, 20 ml of 2 N NaOH and 50 ml ofdichloromethane are added to the filtrate. The organic phase isseparated off, dried over sodium sulfate and evaporated. The residue ischromatographed on a silica gel column with dichloromethane/methanol:3-[6-oxo-1-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-1,6-dihydropyridazin-3-yl]benzonitrileas beige crystals; ESI 529;

¹H-NMR (d₆-DMSO): δ [ppm]=1.68 (m, 4H), 2.49 (m, 2H), 2.88 (m, 2H), 3.32(m, 2H), 4.28 (t, J=6.8 Hz, 2H), 5.48 (s, 2H), 7.17 (d, J=10 Hz, 1H),7.52 (t, J=7.3 Hz, 1 H), 7.55 (m, 1 H), 7.73 (t, J=7.8 Hz, 1 H), 7.94(d, J=8 Hz, 1H), 8.09 (s, 1H), 8.19 (d, J=10 Hz, 1H), 8.26 (d, J=8 Hz,1H), 8.33 (dt, J₁=7.2 Hz, J₂=1.8 Hz, 1H), 8.39 (t, J=1.8 Hz, 1 H), 8.43(s, 1H), 8.48 (bs, 1H), 9.14 (s, 2H).

The following compounds are obtained analogously

Compound ESI No. Name and/or structure [M + H]⁺ “A169”6-(1-methyl-1H-pyrazol-4-yl)-2-(3-{5-[1-(2-pyr-rolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}-benzyl)-2H-pyridazin-3-one

508 ¹H-NMR (d₆-DMSO): δ [ppm] = 1.68 (m, 4H), 2.50 (m, 2H), 2.88 (m,2H), 3.31 (m, 2H), 3.88 (s, 3H), 4.28 (t, J = 6.8 Hz, 2H), 5.37 (s, 2H),7.07 (d, J = 9.5 Hz, 1H), 7.50 (m, 2H), 7.83 (d, J = 9.5 Hz, 1H), 7.91(s, 1H), 8.10 (s, 1H), 8.23 (s, 1H), 8.32 (d, J = 7.3 Hz, 1H), 8.38 (bs,1H), 8.44 (s, 1H), 9.14 (s, 2H). “A170”6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H- pyridazin-3-one

556 “A171” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-dimethylamino-ethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H- pyridazin-3-one

514 “A172” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(3-dimethylamino- 528propyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H- pyridazin-3-one“A173” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-pyrrolidin-1-yl- 540ethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H- pyridazin-3-one “A174”3-[1-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin- 3-yl]benzonitrile

545 ¹H-NMR (d₆-DMSO): δ [ppm] = 2.43 (m, 4H), 2.75 (t, J = 6.5 Hz, 2H),3.56 (m, 4H), 4.29 (t, J = 6.5 Hz, 2H), 5.47 (s, 2H), 7.17 (d, J = 10Hz, 1H), 7.53 (m, 2H), 7.72 (t, J = 7.8 Hz, 1H), 7.93 (dt, J₁ = 7.7, J₂= 1.3 Hz, 1H), 8.09 (s, 1H), 8.18 (d, J = 10 Hz, 1H), 8.26 (d, J = 8 Hz,1H), 8.32 (dt, J₁ = 7 Hz, J₂ = 1.5 Hz, lH), 8.38 (t, J = 1.6 Hz, 1H),8.42 (s, 1H), 8.47 (bs, 1H), 8.13 (s, 2H) “A175”2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}benzyl)-6-pyridin-3-yl-2H-pyridazin-3- one,trifluoroacetate

521 “A176” 6-(1-methyl-1H-pyrazol-4-yl)-2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H- pyridazin-3-one,trifluoroacetate

524 “A177” 2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]- 521pyrimidin-2-yl}benzyl)-6-pyridin-4-yl-2H-pyridazin-3- one,trifluoroacetate “A178” 6-(4-methanesulfonylphenyl)-2-(3-{5-[1-(2-mor-598 pholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}-benzyl)-2H-pyridazin-3-one, hydrochloride “A179”6-pyridin-4-yl-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H- 505pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3- one ¹H-NMR(d₆-DMSO): δ [ppm] = 1.75 (b, 4H), 2.68 (b, 4H), 3.1 (b, 2H), 4.36 (b,2H), 5.49 (s, 2H), 7.19 (d, J = 9.5 Hz, 1H), 7.54 (m, 2H), 7.91 (d, J =6.5 Hz, 2H), 8.14 (bs, 1H), 8.18 (d, J = 9.5 Hz, 1H), 8.33 (dt, J₁ = 6.5Hz, J₂ = 1.8 Hz, 1H), 8.46 (m, 2H), 8.72 (d, J =6.5 Hz, 2H), 9.15 (s,2H) “A180” 4-[6-oxo-1-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-1,6-dihydropyridazin-3-yl]- benzonitrile

529 ¹H-NMR (d₆-DMSO): δ [ppm] = 1.68 (m, 4H), 2.51 (m, 4H), 2.90 (m,2H), 4.28 (m, 2H), 5.47 (s, 2H), 7.17 (d, J = 9.5 Hz, 1H), 7.52 (m, 2H),7.98 (d, J = 9 Hz, 2H), 8.10 (s, 1H), 8.12 (d, J = 9 Hz, 2H), 8.17 (d, J= 9.5 Hz, 1H), 8.38 (dt, J₁ =6.5 Hz, J₂ =1.8 Hz, 1H), 8.44 (s, 1H), 8.45(bs, 1H), 9.13 (s, 2H) “A181”2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]- 521pyrimidin-2-yl}benzyl)-6-pyridin-4-yl-2H-pyridazin-3-one “A182”

421 “A183” 6-(4-methanesulfonylphenyl)-2-(3-{5-[1-(2-morpholin-4- 598ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H- pyridazin-3-one“A184” 6-(5-methyloxazol-2-yl)-2-(3-{5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H- pyridazin-3-one

509 “A185” 6-(3-fluorophenyl)-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-522 pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one “A186”6-(1-propyl-1H-pyrazol-4-yl)-2-(3-{5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H- pyridazin-3-one

536 “A187” 2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}benzyl)-6-thiophen-3-yl-2H-pyridazin-3- one

510 “A188”

“A188a”

EXAMPLE 37

The preparation of the compound3-(1-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“A189”) is carried out analogously to the following scheme

37.1 1382 g (10.0 mol) of potassium carbonate are added in portions withstirring to a suspension, held at 30° C., of 500 g (3.40 mol) of3-cyanobenzoic acid in 8 l of methanol. 695 g (10.0 mol) ofhydroxylammonium chloride are subsequently added in small portions at aninternal temperature of 40-45° C. The reaction mixture is then heated atthe boil for 15 hours. The reaction mixture is evaporated in vacuo, andthe residue is dissolved in water and acidified using 37% aqueoushydrochloric acid. The resultant precipitate is filtered off withsuction, washed with water and dried in vacuo:3-(N-hydroxycarbamimidoyl)benzoic acid as colourless crystals; ESI 181.

37.2 A mixture of 614 g (3.41 mol) of 3-(N-hydroxycarbamimidoyl)benzoicacid, 756 ml (8.0 mol) of acetic anhydride and 2 l of acetic acid isheated at a temperature of 118° C. for 14 hours. The reaction mixture iscooled to 6° C. and filtered with suction. The residue is taken up in 2l of water, filtered off with suction and washed well with water. Theresidue is recrystallised from ethanol/water:3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid as colourless crystals;m.p. 225° C.; ESI 205.

37.3 7.83 ml (147 mmol) of concentrated sulfuric acid are added to asuspension of 30.0 g (147 mmol) of3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid in 150 ml of methanol, andthe mixture is heated at the boil for 18 hours. The reaction mixture iscooled in an ice bath, water is added, and the solid is filtered offwith suction and washed well with water: methyl3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate as colourless crystals; ESI219.

37.4 150 ml of acetic acid, 150 ml of water and 50 g of water-moistRaney nickel are added to a solution of 327 g (1.47 mol) of methyl3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate in 3 l of methanol, and themixture is hydrogenated at room temperature and atmospheric pressure for18 hours. The catalyst is filtered off, and the filtrate is evaporated.The residue is taken up in tert-butyl methyl ether, heated to the boiland filtered off with suction. The residue is dried in vacuo:3-methoxycarbonylbenzamidinium acetate as colourless crystals; ESI 179.

37.5 2.2 l of a freshly prepared 1.5 M sodium methoxide solution areadded dropwise with stirring to a suspension of 259 g (1.09 mol) of3-methoxycarbonylbenzamidinium acetate and 528 g (1.08 mol) of({2-dimethylamino-1-[dimethylimmoniomethyl]vinylamino}methylene)dimethylammoniumdihexafluorophosphate (prepared in accordance with C. B. Dousson et al.,Synthesis 2005, 1817) in 1 l of methanol. The reaction mixture is thenwarmed to 60° C. over the course of 40 min and held at this temperaturefor 30 min. The reaction mixture is then cooled to room temperature,diluted with 10 l of dichloromethane and washed three times with 5 l ofwater each time. The organic phase is dried over sodium sulfate andevaporated. The residue is recrystallised from ethyl acetate: methyl3-[5-(dimethylaminomethyleneamino)pyrimidin-2-yl]benzoate as beigecrystals; m.p. 140° C., ESI 285

37.6 160 ml (2.88 mol) of concentrated sulfuric acid are added to asuspension of 103.5 g (364 mmol) of methyl3-[5-(dimethylaminomethyleneamino)pyrimidin-2-yl]benzoate in 1.3 l ofwater, and the mixture is heated at the boil for 4 hours. The reactionmixture is cooled to room temperature, diluted with water and filteredwith suction. The residue is washed with water and dried in vacuo:3-(5-hydroxypyrimidin-2-yl)benzoic acid as brownish crystals; ESI 217.

37.7 32.7 ml (445 mmol) of thionyl chloride are added to a suspension of88.0 g (366 mmol) of 3-(5-hydroxypyrimidin-2-yl)benzoic acid in 1.4 l ofmethanol, and the mixture is heated at 80° C. for 2 hours. 20 ml (276mmol) of thionyl chloride are then added, and, after 2 hours, a further10 ml (138 mmol) of thionyl chloride are then added. After eachaddition, the reaction mixture is stirred at 80° C. for 2 hours. Thereaction mixture is concentrated in vacuo to a volume of about 300 ml.The resultant precipitate is filtered off and dried in vacuo: methyl3-(5-hydroxypyrimidin-2-yl)benzoate as brownish crystals; ESI 231.

37.8 A solution, kept under nitrogen, of 6.1 g (26.5 mmol) of methyl3-(5-hydroxypyrimidin-2-yl)benzoate, 10.5 g (39.8 mmol) oftriphenylphosphine and 4.76 ml (39.8 mmol) of3-(dimethylamino)-1-propanol in 200 ml of THF is cooled in an ice bath,and 8.21 ml (39.8 mmol) of diisopropyl azodicarboxylate are slowly addeddropwise with stirring. After the reaction mixture has been stirred atroom temperature for 2 hours, it is evaporated in vacuo. The residue ispartitioned between dichloromethane and saturated aqueous potassiumhydrogensulfate solution. The aqueous phase is separated off, adjustedto a pH of 12 using saturated aqueous sodium hydroxide solution andextracted twice with dichloromethane. The organic phase is dried oversodium sulfate and evaporated. The residue is chromatographed on asilica gel column with dichloromethane/methanol as eluent: methyl3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzoate as colourlesscrystals; ESI 316.

37.9 200 ml of a 1 M solution of diisobutylaluminium hydride in THF areadded dropwise with stirring to a solution, kept under nitrogen, of 12.6g (40.0 mmol) of methyl3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzoate in 200 ml of THF.After the mixture has been stirred at room temperature for 1 hour, 10 mlof a saturated aqueous sodium sulfate solution are added dropwise. Theresultant precipitate is filtered off with suction and washed withdichloromethane. The filtrate is dried over sodium sulfate andevaporated. The residue is taken up in a mixture of diethyl ether andpetroleum ether. The resultant precipitate is filtered off with suction,washed with petroleum ether and dried in vacuo:{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]phenyl}methanol ascolourless crystals; m.p. 95-97° C.; ESI 288.

37.10 3.16 g (18.0 mmol) of3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile and 6.36 g (24.0 mmol)of triphenylphosphine are added to a solution of 5.06 g (17.6 mmol) of{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}methanol in 100 mlof THF. The resultant suspension is cooled in an ice bath, and 4.96 ml(24.0 mmol) of diisopropyl azodicarboxylate are slowly added dropwise.After the mixture has been stirred at room temperature for 1 hour,tert-butyl methyl ether and 1 N aqueous hydrochloric acid is added. Theaqueous phase is separated off and washed three times with tert-butylmethyl ether. The aqueous phase is adjusted to a pH of 14 using 2 Nsodium hydroxide solution and extracted twice with dichloromethane. Theorganic phase is dried over sodium sulfate and evaporated. The residuechromatographed on a silica gel column with dichloromethane/methanol:3-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrileas colourless crystals; m.p. 128° C.; ESI 467;

¹H-NMR (d₆-DMSO): δ [ppm]=1.89 (quintet, J=6.8 Hz, 2H), 2.15 (s, 6H),2.37 (t, J=7 Hz, 2H), 4.21 (t, J=6.5 Hz, 2H), 5.44 (s, 2H), 7.16 (d,J=10 Hz, 1H), 7.48 (m, 2H), 7.72 (t, J=7.8 Hz, 1H), 7.92 (dt, J₁=7.5 Hz,J₂=1.2 Hz, 1H), 8.17 (d, J=10 Hz, 1H), 8.23 (m, 2H), 8.37 (t, J=1.6 Hz,1H), 8.39 (bs, 1H), 8.63 (s, 2H).

The following compounds are obtained analogously

“A114”, “A24”,

Compound ESI No. Name and/or structure [M + H]⁺ “A190”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]-benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3- one,trifluoroacetate

446 “A191” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 460benzyl}-6-(3-fluorophenyl)-2H-pyridazin-3-one, hydrochloride “A192”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 449benzyl}-6-thiazol-2-yl-2H-pyridazin-3-one, hydro- chloride “A193”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 442benzyl}-6-phenyl-2H-pyridazin-3-one, hydrochloride “A194”4-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 467benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, hydrochloride“A195” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 456benzyl}-6-p-tolyl-2H-pyridazin-3-one “A196”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 432benzyl}-6-(2H-pyrazol-3-yl)-2H-pyridazin-3-one, trifluoroacetate “A197”6-(3,4-difluorophenyl)-2-{3-[5-(3-dimethylamino- 478propoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, hydrochloride “A198”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 520benzyl}-6-(4-methanesulfonylphenyl)-2H-pyridazin-3- one, hydrochloride“A199” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 524benzyl}-6-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]- 2H-pyridazin-3-one,hydrochloride “A200” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]-443 benzyl}-6-pyridin-4-yl-2H-pyridazin-3-one, trifluoroacetate “A201”6-(3-bromophenyl)-2-{3-[5-(3-dimethylaminopropoxy)- 521pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, trifluoroacetate “A202”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 496benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one “A203”6-(3,5-dimethoxyphenyl)-2-{3-[5-(3-dimethylamino- 502propoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, trifluoroacetate“A204” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 490benzyl}-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3- one, hydrochloride“A205” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 472benzyl}-6-(4-methoxyphenyl)-2H-pyridazin-3-one, hydrochloride “A206”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 510benzyl}-6-(3-trifluoromethylphenyl)-2H-pyridazin-3- one, hydrochloride“A207” 6-(3-chlorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)- 476pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A208”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 443benzyl}-6-pyridin-3-yl-2H-pyridazin-3-one “A209”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 446benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3- one “A210”6-(3-chloro-5-fluorophenyl)-2-{3-[5-(3-dimethylamino- 494propoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one ¹H-NMR (d₆-DMSO): δ[ppm] = 1.89 (quintet, J = 6.7 Hz, 2H), 2.16 (s, 6H), 2.38 (t, J = 7 Hz,2H), 4.21 (t, J = 6.5 Hz, 2H), 5.44 (s, 2H), 7.14 (d, J = 10 Hz, 1H),7.48 (m, 2H), 7.54 (dt, J₁ =8.5 Hz, J₂ = 2 Hz, 1H), 7.77 (dt, J₁ =10 Hz,J₂ =1.7 Hz, 1H), 7.85 (t, J = 1.6 Hz, 1H), 8.15 (d, J = 10 Hz, 1H), 8.23(m, 1H), 8.37 (bs, 1H), 8.62 (s, 2H) “A211”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 490benzyl}-6-(4-fluoro-3-methoxyphenyl)-2H-pyridazin-3- one, hydrochloride“A212” 6-(4-chlorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)- 476pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, trifluoroacetate “A213”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 460benzyl}-6-(4-fluorophenyl)-2H-pyridazin-3-one, trifluoroacetate “A214”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 448benzyl}-6-thiophen-2-yl-2H-pyridazin-3-one, trifluoroacetate “A215”N-[4-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)phenyl]- acetamide,trifluoroacetate

499 “A216” 6-(3,4-dimethoxyphenyl)-2-{3-[5-(3-dimethylamino- 502propoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, trifluoroacetate“A217” 6-benzo-2,1,3-thiadiazol-5-yl-2-{3-[5-(3-dimethyl-aminopropoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3- one

500 “A218” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]-benzyl}-6-turan-3-yl-2H-pyridazin-3-one, trifluoro- 432 acetate “A219”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]- 448benzyl}-6-(5-methyl-1,2,4-oxadiazol-3-yl)-2H- pyridazin-3-one,hydrochloride “A220”4-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]- 479benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A221”3-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]- 479benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, hydrochloride“A222” 3-(1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]- 495benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A223”2-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]- 455benzyl}-6-pyridin-4-yl-2H-pyridazin-3-one “A224”6-(4-methanesullonylphenyl)-2-{3-[5-(1-methyl 532piperidin-4-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin- 3-one,trifluoroacetate “A225” methyl5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thio- phene-2-carboxylate,trifluoroacetate

518 “A226” 2-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]- 458benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3- one ¹H-NMR(d₆-DMSO): δ [ppm] = 1.70 (m, 2H), 2.00 (m, 2H), 2.22 (s, 3H), 2.24 (m,2H), 2.66 (m, 2H), 3.88 (s, 3H), 4.62 (m, 1H), 5.34 (s, 2H), 7.06 (d, J= 9.5 Hz, 1H), 7.44 (dt, J₁ =7.3 Hz, J₂ =1.5 Hz, 1H), 7.48 (t, J = 7.5Hz, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.90 (s, 1H), 8.22 (m, 2H), 8.25 (s,1H), 8.28 (bs, 1H), 8.65 (s, 2H) “A227”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]-benzyl}-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 2H-pyridazin-3-one,trifluoroacetate

450 “A228” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]-benzyl}-6-piperazin-1-yl-2H-pyridazin-3-one, trifluoroacetate

[preparation proceeds via Boc-protected compound and subsequent removalof the Boc group] 450

EXAMPLE 38

The preparation of the compounds

6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“A229”),

2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“A230”) and

2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“A231”)

is carried out analogously to the following scheme

38.1 12.4 g (43.6 mmol) of 5-bromo-2-(3-chloromethylphenyl)pyrimidineand 14.2 g (43.6 mmol) of caesium carbonate are added to a suspension of7.68 g (43.6 mmol) of 6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one in90 ml of DMF, and the mixture is stirred at room temperature for 24hours. The reaction mixture is added to 400 ml of water. The resultantprecipitate is filtered off with suction, washed with water and dried invacuo;2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-oneas yellow-brown crystals; m.p. 184° C.; ESI 423, 425.

38.2 10.9 g (42.9 g) of bis(pinacolato)diboron and 9.72 g (99.0 mmol) ofpotassium acetate are added to a suspension of 14.0 g (33.0 mmol) of2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-onein 65 ml of DMF, and the mixture is heated to 70° C. under nitrogen.After the mixture has been stirred at this temperature for 15 minutes,695 mg (0.99 mmol) of bis(triphenylphosphine)palladium(II) chloride areadded, and the reaction mixture is stirred at 70° C. under nitrogen for18 hours. The reaction mixture is allowed to cool to room temperature,water and dichloromethane are added, the mixture is filtered throughkieselguhr, and the organic phase is separated off. The organic phase isdried over sodium sulfate and evaporated, and the residue isrecrystallised from 2-propanol:6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-oneas grey crystals; m.p. 204° C.;

¹H-NMR (d₆-DMSO): δ [ppm]=1.34 (s, 12H), 3.87 (s, 3H), 5.35 (s, 2H),7.05 (d, J=9.6 Hz, 1H), 7.52 (m, 2H), 7.80 (d, J=9.6 Hz, 1H), 7.89 (s,1H), 8.21 (s, 1H), 8.35 (m, 1H), 8.45 (bs, 1 H), 9.01 (s, 2H).

38.3 8.50 g (85.1 mmol) of sodium perborate are added in portions withice cooling to a suspension of 13.4 g (28.4 mmol) of6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-onein 55 ml of THF and 55 ml of water, and the mixture is stirred at roomtemperature for 2 hours. The reaction mixture is filtered throughkieselguhr with suction. The filtrate is concentrated in vacuo to abouthalf the original volume and adjusted to a pH of 1 using 2 Nhydrochloric acid. The resultant precipitate is filtered off withsuction, washed with water and dried in vacuo:2-[3-(5-hydroxypyrimidin-2-yl)-benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-oneas pale-beige crystals; m.p. 239° C.; ESI 361.

38.4 394 mg (1.50 mmol) of triphenylphosphine and 242 μl (2.00 mmol) of4-(2-hydroxyethyl)morpholine are added successively to a suspension of360 mg (1.00 mmol) of2-[3-(5-hydroxypyrimidin-2-yl)-benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-onein 2 ml of THF. 294 μl (1.50 mmol) of diisopropyl azodicarboxylate arethen slowly added dropwise with ice cooling. The resultant solution isstirred at room temperature for 18 hours. The reaction mixture isevaporated in vacuo, and the oily residue is dissolved in 2-propanol.The solid formed after some time is filtered off with suction, washedwith 2-propanol and tert-butyl methyl ether and dried in vacuo:6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“A229”) as colourless crystals; m.p. 134° C.; ESI 474;

¹H-NMR (d₆-DMSO): δ [ppm]=2.48 (m, 4H), 2.73 (t, J=5.5 Hz, 2H), 3.57 (m,4H), 3.87 (s, 3H), 4.30 (t, J=5.5 Hz, 2H), 5.33 (s, 2H), 7.05 (d, J=9.5Hz, 1H), 7.43 (dt, J₁=7.3 Hz, J₂=1.5 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H),7.80 (d, J=9.5 Hz, 1H), 7.89 (s, 1 H), 8.21 (s, 1H), 8.22 (dt, J₁=7.5Hz, J₂=1.5 Hz, 1H), 8.28 (bs, 1H), 8.64 (s, 2H).

The p-toluenesulfonate and the phosphate are obtained from “A229” bysalt formation.

The following compounds are obtained analogously

Compound ESI No. Name and/or structure [M + H]⁺ (“A232”)6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-yl- 474ethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, hydrochloride (from“A229”) (“A233”) 2-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]-472 benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3- one,hydrochloride (from “A237”) (“A234”)2-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]- 472benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3- one,trifluoroacetate (from “A237”) “A235”6-(3-fluorophenyl)-2-{3-[5-(2-morpholin-4-ylethoxy)- 488pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A236”6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-yl-ethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, 474 dihydrochloride(from “A229”) “A237”2-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]- 472benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A238”2-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}- 4586-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one, formate “A239”2-[3-(5-methoxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H- 375pyrazol-4-yl)-2H-pyridazin-3-one “A240”2-{3-[5-(3-methoxypropoxy)pyrimidin-2-yl]benzyl}-6-(1- 433methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A241”2-{3-[5-(2-methoxyethoxy)pyrimidin-2-yl]benzyl}-6-(1- 419methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A242”2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-6- 502(1-propyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A243”2-(3-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyrimidin-2-yl}- 487benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A244”2-(3-{5-[2-(4-methyl-3-oxopiperazin-1-yl)ethoxy]-pyrimidin-2-yl}benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-2H- pyridazin-3-one

501 “A245” 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(3-morpholin-4-yl- 488propoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, trifluoroacetate“A246” 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-yl-propoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, trifluoroacetate

488 “A247” 2-{3-[5-(1-methyl-2-morpholin-4-ylethoxy)pyrimidin-2-yl]-benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3- one,trifluoroacetate

488 “A248” 2-{3-[5-(2-dimethylaminoethoxy)pyrimidin-2-yl]benzyl}-6- 432(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A305”

445 “A306” 2-{3-[5-(1-azabicyclo[2.2.2]oct-3-yloxy)pyrimidin-2-yl]-benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one

470 “A307”

514 “A310”

509 “A312”

507 “A314”

505

EXAMPLE 39

Alternative preparation of “A229”

A suspension of 360 mg (1.00 mmol) of2-[3-(5-hydroxypyrimidin-2-yl)-benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one,195 mg (1.05 mmol) of N-(2-chloroethyl)morpholinium chloride and 521 mg(1.60 mmol) of caesium carbonate in 2 ml of DMF is heated to 80° C. withstirring and stirred at this temperature for 6 hours. The reactionmixture is allowed to cool, and 50 ml of water are added. The resultantprecipitate is filtered off with suction, washed with water and dried invacuo:6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-oneas colourless crystals.

The following compounds are obtained analogously

Compound ESI No. Name and/or structure [M + H]⁺ “A249”2-{3-[5-(2-methyl-3-morpholin-4-ylpropoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3- one

502 “A250” 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-pyrrolidin-1-yl- 458ethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A251”2-[3-(5-ethoxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H- 389pyrazol-4-yl)-2H-pyridazin-3-one “A252”6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-yl-2-oxoethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

488 “A253” 6-(3-chlorophenyl)-2-{3-[5-(2-morpholin-4-ylethoxy)- 504pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A254”

“A255”

“A256”

“A304”

418

EXAMPLE 40

The preparation of the compound3-(1-{3-[5-(1-methylpiperidin-4-yl-methoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“A257”) is carried out analogously to the following scheme

40.1 17.7 g (67.8 mmol) of triphenylphosphine are added to a suspensionof 13.0 g (56.5 mmol) of methyl 3-(5-hydroxypyrimidin-2-yl)benzoate and13.4 g (62.1 mmol) of N-Boc-piperidinemethanol in 115 ml of THF, and themixture is cooled to 5° C. 13.3 ml (67.8 mmol) of diisopropylazo-dicarboxylate are added dropwise over the course of 45 minutes withstirring to the suspension held at this temperature. The reactionmixture is stirred at room temperature for 1 hour. A further 22.2 g(84.7 mmol) of triphenylphosphine and 16.6 ml (84.7 mmol) of diisopropylazodicarboxylate are subsequently added. The reaction mixture is stirredat room temperature for 18 hours and evaporated in vacuo. The resultantsolid is filtered off with suction, washed with diethyl ether andchromatographed on a silica gel column with dichloromethane/methanol aseluent: tert-butyl4-[2-(3-methoxycarbonylphenyl)pyrimidin-5-yloxymethyl]piperidine-1-carboxylateas lemon-yellow crystals;

m.p. 166° C.; ESI 428.

40.2 25 ml (25 mmol) of a 1 M solution of diisobutylaluminium hydride inTHF are added dropwise under nitrogen to a suspension of 1.71 g (3.99mmol) of tert-butyl4-[2-(3-methoxycarbonylphenyl)pyrimidin-5-yloxymethyl]piperidine-1-carboxylatein 20 ml of THF. The reaction mixture is stirred at room temperature for1 hour, and 1 ml of a saturated sodium sulfate solution is added. Theresultant precipitate is filtered off with suction and washed with THFand hot 2-propanol. The filtrate is evaporated and recrystallised fromtert-butyl methyl ether:{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]phenyl}methanol asbeige crystals; m.p. 175° C.; ESI 314.

40.3 264 mg (1.30 mmol) of3-(6-oxo-1,6-dihydropyridazin-3-yl)-benzonitrile and 397 mg (1.5 mmol)of triphenylphosphine are added successively to a solution of 313 mg(1.00 mmol) of{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]phenyl}methanol in 2ml of THF. The reaction mixture is cooled in an ice bath, and 294 μl(1.5 mmol) of diisopropyl azodicarboxylate are added dropwise withstirring. The reaction mixture is stirred at room temperature for 18hours and evaporated. The residue is chromatographed on a silica gelcolumn with dichloromethane/methanol. The product-containing fractionsare combined and evaporated, and the residue is digested with tert-butylmethyl ether, filtered off with suction and dried in vacuo:3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrileas colourless crystals; m.p. 177° C.; ESI 493;

¹H-NMR (d₆-DMSO): δ [ppm]=1.33 (m, 2H), 1.75 (m, 3H), 1.89 (m, 2H), 2.17(s, 3H), 2.80 (m, 2H), 4.05 (d, J=6.1 Hz, 2H), 5.45 (s, 2H), 7.16 (d,J=10 Hz, 1H), 7.49 (m, 2H), 7.73 (t, J=7.8 Hz, 1H), 7.93 (d, J=7.8 Hz,1H), 8.17 (d, J=10 Hz, 1H), 8.24 (m, 2H), 8.38 (m, 2H), 8.64 (s, 2H).

The hemisulfate, citrate, tartrate, sulfate, succinate and hydrochlorideare obtained from “A257” by salt formation.

EXAMPLE 41

The preparation of the compounds

2-[3-(5-bromopyridin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one(“A258”) and

6-(3,5-difluorophenyl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyridin-2-yl]benzyl}-2H-pyridazin-3-one(“A259”)

is carried out analogously to the following scheme

41.1 A suspension of 695 mg (1.64 mmol) of6-(3,5-difluorophenyl)-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-2H-pyridazin-3-one(preparation see Example 11), 427 mg (1.80 mmol) of 2,5-dibromopyridineand 695 mg (3.28 mmol) of tripotassium phosphate trihydrate in 10 ml of1,2-dimethoxyethane is heated to 80° C. under nitrogen. 92 mg (0.13mmol) of bis(triphenylphosphine)palladium(II) chloride are then added,and the reaction mixture is stirred at 80° C. for 18 hours. The reactionmixture is allowed to cool, and water is added. The resultantprecipitate is filtered off with suction, washed with water and dried:2-[3-(5-bromopyridin-2-yl)-benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-oneas yellowish crystals; ESI 453, 455.

41.2 A suspension of 333 mg (0.732 mmol) of2-[3-(5-bromopyridin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one,304 mg (0.805 mmol) of tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-piperidine-1-carboxylateand 311 mg (1.46 mmol) of tripotassium phosphate trihydrate in 2 ml of1,2-dimethoxyethane is heated to 80° C. under nitrogen. 43 mg (0.06mmol) of bis(triphenylphosphine)palladium(II) chloride are then added,and the reaction mixture is stirred at 80° C. for 2 hours. The reactionmixture is allowed to cool, and water is added. The resultantprecipitate is filtered off with suction and washed with water. Theresidue is recrystallised from 2-propanol: tert-butyl4-[4-(6-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyridin-3-yl)pyrazol-1-yl]piperidine-1-carboxylateas grey crystals; ESI 625.

41.3 5 ml of 4 N HCl in dioxane are added to 347 mg (0.556 mmol) oftert-butyl4-[4-(6-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}pyridin-3-yl)pyrazol-1-yl]piperidine-1-carboxylate.The resultant precipitate is filtered off and dissolved in a mixture of2 N sodium hydroxide solution and dichloromethane. The organic phase isseparated off, dried over sodium sulfate and evaporated. The residue isrecrystallised from 2-propanol:6-(3,5-difluorophenyl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyridin-2-yl]benzyl}-2H-pyridazin-3-oneas pale-yellow crystals; ESI 525;

¹H-NMR (d₆-DMSO): δ [ppm]=1.82 (m, 2H), 2.00 (m, 2H), 2.07 (bs, 1H),2.61 (m, 2H), 3.06 (m, 2H), 4.22 (m, 1H), 5.45 (s, 2H), 7.15 (d, J=9.5Hz, 1H), 7.35 (m, 1H), 7.42 (d, J=7.5 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H),7.67 (m, 2H), 7.93 (d, J=8 Hz, 1H), 8.02 (m, 2H), 8.06 (d, J=8 Hz, 1H),8.15 (d, J=9.5 Hz, 1H), 8.19 (bs, 1H), 8.39 (s, 1H), 8.93 (bs, 1H).

EXAMPLE 42

The preparation of the compounds

3-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzamide(“A260”) and of “A261”

is carried out analogously to the following scheme

EXAMPLE 43

The preparation of the compounds

3-{1-[3-(5-bromopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}-benzonitrile(“A262”),

3-{1-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}-benzonitrile(“A263”),

3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile(“A264”),

tert-butyl4-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yloxymethyl)piperidine-1-carboxylate(“A265”) and the alternative synthesis of “A257”

are carried out analogously to the following scheme

43.1 6.00 g (21 mmol) of 5-bromo-2-(3-chloromethylphenyl)pyrimidine and2.76 g (341 mmol) of potassium carbonate are added to a suspension of4.15 g (20 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile in40 ml of 1-methyl-2-pyrrolidone, and the mixture is stirred at 80° C.for 18 hours. The reaction mixture is added to 200 ml of water. Theresultant precipitate is filtered off with suction, washed with waterand dried in vacuo:3-{1-[3-(5-bromopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}-benzonitrile(“A262”) as beige crystals, ESI 444, 446.

43.2 11.8 g (47 mmol) of bis(pinacolato)diboron and 11.9 g (122 mmol) ofpotassium acetate are added to a solution of 18.0 g (41.0 mmol) of3-{1-[3-(5-bromopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrilein 85 ml of DMF, and the mixture is heated to 80° C. under nitrogen.After the mixture has been stirred at this temperature for 15 minutes,273 mg (1.22 mmol) of palladium(II) acetate are added, and the reactionmixture is stirred at 80° C. under nitrogen for 2 hours. The reactionmixture is allowed to cool to room temperature, water anddichloromethane are added, the mixture is filtered through kieselguhr,and the organic phase is separated off. The organic phase is dried oversodium sulfate and evaporated:3-(6-oxo-1-{3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrileas grey solid, which is employed in the subsequent reaction withoutfurther purification.

43.3 4.93 g (49.4 mmol) of sodium perborate are added in portions withice cooling to a suspension of 5.33 g (10.9 mmol) of3-(6-oxo-1-{3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrilein 35 ml of THF and 35 ml of water, and the mixture is stirred at roomtemperature for 2 hours. 300 ml of dichloromethane and 100 ml ofsaturated ammonium chloride solution are added to the reaction mixture.The organic phase is separated off, dried over sodium sulfate andevaporated. The residue is recrystallised from methanol:3-{1-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile(“A263”) as brownish solid; m.p. 248° C.; ESI 382.

43.4 15.6 g (68.8 mmol) of N-Boc-4-piperidinemethanol and 19.1 g (72.1mmol) of triphenylphosphine are added successively to a suspension of 25g (65.6 mmol) of3-{1-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrilein 250 ml of THF. 14.9 ml (72.1 mmol) of diisopropyl azodicarboxylateare then slowly added dropwise with ice cooling. The resultant solutionis stirred at room temperature for a further 2 hours. 750 ml of2-propanol and 13.1 ml of a 0.5 M solution of potassium hydroxide inethanol are added to the reaction mixture. The resultant precipitate isfiltered off with suction, washed with diethyl ether and dried in vacuo:tert-butyl4-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}pyrimidin-5-yloxymethyl)piperidine-1-carboxylate(“A265”) as colourless crystals; m.p. 178° C.; ESI 579.

43.5 A solution of 1.22 g (2.10 mmol) of tert-butyl4-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxymethyl)-piperidine-1-carboxylatein 12 ml of a 4 N solution of hydrogen chloride in dioxane is stirred atroom temperature for 16 h, during which an insoluble precipitate forms.The supernatant solution is decanted off. Dichloromethane and asaturated sodium hydrogencarbonate solution are added to the residue.The organic phase is separated off, dried over sodium sulfate andevaporated in vacuo. The residue is chromatographed on a silica gelcolumn with dichloromethane/methanol:3-(6-oxo-1-{3-[5-(piperidin-4-yl-methoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile(“A264”) as colourless crystals; ESI 479.

43.6 6.60 ml of 35% aqueous formaldehyde solution are added to asolution of 16.0 g (28.0 mmol) of tert-butyl4-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxymethyl)piperidine-1-carboxylatein 80 ml of formic acid, and the mixture is stirred at a temperature of110° C. for 2 hours. 300 ml of water are added to the reaction mixture,which is then concentrated in vacuo to a volume of 150 ml. The mixtureis extracted with 200 ml of dichloromethane. The organic phase is washedwith sodium hydrogencarbonate solution, dried over sodium sulfate andevaporated. The residue is recrystallised from 2-propanol:3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“A257”) as colourless crystals; m.p. 177° C., ESI 493.

The following compounds are obtained analogously

Compound ESI No. Name and/or structure [M + H]⁺ “A266”6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(piperidin-4-yloxy)- 444pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A267”6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(piperidin-4-yl- 458methoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A268”3-(1-{3-[5-(3-methylaminopropoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, hydrochloride

453 “A269” 3-[1-(3-{5-[2-(4-methyl-3-oxopiperazin-1-yl)ethoxy]-pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]- benzonitrile

522 “A270” 3-[1-(3-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyrimidin- 5082-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]- benzonitrile “A271”3-(1-{3-[5-(2-methoxyethoxy)pyrimidin-2-yl]benzyl}-6- 440oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A272”3-(1-{3-[5-(3-methoxypropoxy)pyrimidin-2-yl]benzyl}-6- 454oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A273”6-(3-fluorophenyl)-2-{3-[5-(1-methylpiperidin-4-yl- 486methoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A274”2-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]- 486benzyl}-6-(1-propyl-1H-pyrazol-4-yl)-2H-pyridazin-3- one ¹H-NMR(d₆-DMSO): δ [ppm] = 0.83 (t, J = 7.4 Hz, 3H), 1.69 (m, 2H), 1.80(sextet, J = 7.2 Hz, 2H), 1.98 (m, 2H), 2.20 (s, 3H), 2.22 (m, 2H), 2.63(m, 2H), 4.09 (t, J = 6.8 Hz, 2H), 4.60 (m, 1H), 5.34 (s, 2H), 7.05 (d,J = 9.5 Hz, 1H), 7.43 (dt, J₁ = 7.3 Hz, J₂ = 1.5 Hz, 1H), 7.47 (t, J =7.5 Hz, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.90 (s, 1H), 8.21 (dt, J₁ = 7.5Hz, J₂ = 1.5 Hz, 1H), 8.25 (s, 1H), 8.28 (bs, 1H), 8.64 (s, 2H) “A275”6-(3-chlorophenyl)-2-{3-[5-(1-methylpiperidin-4-yl- 503methoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A276”

“A276a”

EXAMPLE 44

44.1 Preparation of5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2-carboxylicacid (“A277”)

2 g (3.85 mmol) of methyl5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2-carboxylate(“A225”) are dissolved in 50 ml of THF and 5 ml of water, and 283 mg(11.6 mmol) of lithium hydroxide are added. The solution is stirred atroom temperature for 15 h. The reaction mixture is evaporated, and theresidue is dissolved in 200 ml of water and extracted with 200 ml ofethyl acetate by shaking. The aqueous phase is washed with 2×200 ml ofethyl acetate. The organic phase is discarded, and the aqueous phase isadjusted to pH 7-8 using 1 N HCl and extracted with 2×300 ml of ethylacetate. The organic phase is dried over sodium sulfate and evaporatedto dryness;

yield: 1.2 g of “A277”; HPLC: Rt=2.27 min; LC-MS: 504 (M+H).

44.2 Preparation of5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2-carboxamide(“A278”)

150 mg (0.30 mmol) of5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2-carboxylicacid (“A277”) are suspended in 2 ml of DMF, and 1 ml (5.9 mmol) of 10%ammonia solution in THF, 67 μl (0.60 mmol) of N-methylmorpholine, 115 mg(0.60 mmol) of EDCl and 41 mg (0.30 mmol) of HOBt are added, and themixture is stirred at room temperature for 15 h. The reaction mixture isevaporated and purified by means of preparative HPLC; yield: 10 mg of“A278” trifluoroacetate, white solid; HPLC: Rt=2.15 min; LC-MS: 503(M+H).

44.3 Preparation ofN-methyl-5-(1-{3-[5-(1-methylpiperidin-4-yloxy)-pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2-carboxamide(“A279”)

150 mg (0.30 mmol) of5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2-carboxylicacid (“A277”) are suspended in 2 ml of DMF, and 205 mg (2.98 mmol) ofmethylamine hydrochloride, 67 μl (0.60 mmol) of N-methylmorpholine, 115mg (0.60 mmol) of EDCl, 41 mg (0.30 mmol) of HOBt and 1.01 ml (5.96mmol) of N-ethyldiisopropylamine are added, and the mixture is stirredat room temperature for 15 h. A further 205 mg (2.98 mmol) ofmethylamine hydrochloride, 67 μl (0.60 mmol) of N-methylmorpholine, 115mg (0.60 mmol) of EDCl, 41 mg (0.30 mmol) of HOBt and 1.01 ml (5.96mmol) of N-ethyldiisopropylamine are added, and the mixture is stirredat room temperature for 15 h. The reaction mixture is evaporated, andthe residue is purified by means of preparative HPLC; yield: 99 mg of“A279” trifluoroacetate, white solid; HPLC: Rt=2.22 min; LC-MS: 517(M+H).

EXAMPLE 45

Preparation of2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2H-pyridazin-3-one(“A227”)

500 mg (1.18 mmol) of1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]-benzyl}-N-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxamidineare dissolved in 15 ml of DMF, and 286 μl (3.54 mmol) of pyridine areadded. 124 μl (1.30 mmol) of ethyl chloroformate are subsequently addedwith stirring, and the solution is stirred at 80° C. for 15 andsubsequently at 100° C. for 72 h. The reaction mixture is evaporated,and the residue is purified by means of preparative HPLC; yield: 21.2 mgof “A227” trifluoroacetate; HPLC: Rt=2.07 min; LC-MS: 450 (M+H).

EXAMPLE 46

Preparation of2-[3-(5-aminopyrazin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one(“A280”)

5 ml of water and 5 ml of acetonitrile are added to 150 mg (0.35 mmol)of6-(3,5-difluorophenyl)-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl]-2H-pyridazin-3-one,63 mg (0.35 mmol) of 5-bromopyrazin-2-yl-amine and 167 mg (1.99 mmol) ofsodium hydrogencarbonate, and the mixture is degassed a number of times.Under an argon atmosphere, 20 mg (0.017 mmol) oftetrakis(triphenylphosphine)palladium(0) are added, and the mixture issubsequently heated at 80° C. for 15 h with stirring. A further 20 mg(0.017 mmol) of tetrakis(triphenylphosphine)palladium(0) aresubsequently added, and the mixture is stirred at 80° C. for a further24 h. The hot suspension is filtered. The filtrate is concentrated tohalf. After cooling to room temperature, the resultant precipitate isfiltered off with suction and washed with a little water. The residue ispurified by means of preparative HPLC; yield: 21 mg of “A280”; HPLC:Rt=2.68 min (method C); LC-MS: 392 (M+H).

The following compounds are obtained analogously

Compound ESI No. Name and/or structure [M + H]⁺ “A281”6-(3,5-difluorophenyl)-2-[3-(6- 391 methylpyridazin-3-yl)-benzyl]-2H-pyridazin-3-one “A282” 2-[3-(6-aminopyridazin-3-yl)benzyl]- 3926-(3,5-difluoro-phenyl)-2H-pyridazin-3-one

EXAMPLE 47

Preparation of methyl(E)-3-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)acrylate(“A283”)

47.1 100 mg (0.38 mmol) of [3-(5-bromopyrimidin-2-yl)phenyl]methanol and51 μl (0.56 mmol) of methyl acrylate are suspended in 2 ml of DMF, and20 mg (0.075 mmol) of triphenylphosphine, 222 mg (2.26 mmol) ofpotassium acetate and 157 mg (0.57 mmol) of tetra-n-butylammoniumchloride are added. The reaction mixture is degassed and flushed withargon, and 17 mg (0.075 mmol) of palladium(II) acetate are added underan argon atmosphere. The mixture is heated at 80° C. for 2 h. Aftercooling, water is added, during which a pale-grey precipitate forms.This is filtered off with suction, washed with water and dried in vacuo.The product is reacted further without further purification; yield: 111mg: HPLC: Rt=2.42 min (method C); LC-MS: 271 (M+H).

47.2 90 mg (0.4 mmol) of 6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-oneand 111 mg (0.41 mmol) of methyl(E)-3-[2-(3-hydroxymethylphenyl)-pyrimidin-5-yl]acrylate are suspendedin 3 ml of THF with 200 mg (0.6 mmol) of polymer-boundtriphenylphosphine (about 3 mmol of triphenylphosphine per g), and themixture is shaken at room temperature for 30 min. The mixture is cooledto 0° C., and 95 μl (0.6 mmol) of diethyl azodicarboxylate are added.The reaction mixture is shaken at room temperature for 24 h. Thereaction mixture is purified by means of preparative HPLC; yield: 7 mgof “A283”; HPLC: Rt=3.41 min (method C);

LC-MS: 479 (M+H).

EXAMPLE 48

Preparation of2-{3-[5-((E)-3-aminopropenyl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one(“A284”)

48.1 812 mg (3.06 mmol) of [3-(5-bromopyrimidin-2-yl)phenyl]methanol and722 mg (4.59 mmol) of tert-butyl N-allylcarbamate are suspended in 16 mlof DMF, and 160 mg (0.61 mmol) of triphenylphosphine, 1.8 g (4.6 mmol)of potassium acetate and 1.28 g (4.59 mmol) of tetra-n-butyl-ammoniumchloride are added. The reaction mixture is degassed and flushed withargon, and 137 mg (0.0.61 mmol) of palladium(II) acetate are added underan argon atmosphere. The mixture is heated at 80° C. for 2 h. Aftercooling, the mixture is filtered through kieselguhr with suction, andthe filtrate is added to water and extracted with 2×100 ml of ethylacetate, dried over sodium sulfate and evaporated. The product wasreacted further without further purification; yield: 380 mg; HPLC:Rt=2.66 min (method C); LC-MS: 342 (M+H).

48.2 66 mg (0.29 mmol) of 6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-oneand 142 mg (0.29 mmol) of tert-butyl{(E)-3-[2-(3-hydroxymethylphenyl)-pyrimidin-5-yl]allyl}carbamate aresuspended in 3 ml of THF with 145 mg (0.44 mmol) of polymer-boundtriphenylphosphine (about 3 mmol of triphenylphosphine per g), and themixture is shaken at room temperature for 30 min. The mixture is cooledto 0° C., and 69 μI (0.44 mmol) of diethyl azodicarboxylate are added.The reaction mixture is shaken at room temperature for 24 h. Thereaction mixture is purified by means of preparative HPLC: yield: 28 mg;HPLC: Rt=3.50 min (method C); LC-MS: 550 (M+H).

48.3 28 mg (0.051 mmol) of tert-butyl[(Z)-3-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)allyl]carbamateare dissolved in 4 ml of dichloromethane, and 79 μl (1.02 mmol) oftrifluoroacetic acid are added. The reaction mixture is stirred at roomtemperature for 15 h and evaporated. The residue is purified by means ofpreparative HPLC; yield: 11 mg of “A284” trifluoroacetate; HPLC: Rt=2.64min (method C); LC-MS: 450 (M+H).

EXAMPLE 49

Preparation of2-{3-[5-(3-aminopropyl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one(“A285”)

49.1 280 mg (0.82 mmol) of tert-butyl{(E)-3-[2-(3-hydroxymethyl-phenyl)pyrimidin-5-yl]allyl}carbamate aredissolved in 10 ml of THF and shaken with 300 mg of platinum onactivated carbon (5%, contains 56% of water) under a hydrogen atmosphereat room temperature for 17 h. The catalyst is filtered off with suction,and the filtrate is evaporated to dryness; yield: 289 mg; HPLC: Rt=2.60min (method C) LC-MS: 344 (M+H).

49.2 195 mg (0.86 mmol) of 6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-oneand 369 mg (0.86 mmol) of tert-butyl{3-[2-(3-hydroxymethylphenyl)pyrimidin-5-yl]propyl}carbamate aresuspended in 10 ml of THF with 430 mg (1.29 mmol) of polymer-boundtriphenylphosphine (about 3 mmol of triphenylphosphine per g) and shakenat room temperature for 30 min. The mixture is cooled to 0° C., and 297mg (0.1.29 mmol) of di-tert-butyl azodicarboxylate are added. Thereaction mixture is shaken at room temperature for 24 h. A further 430mg (1.29 mmol) of polymer-bound triphenylphosphine (about 3 mmol oftriphenylphosphine per g) and 297 mg (1.29 mmol) of di-tert-butylazodicarboxylate are added, and the reaction mixture is shaken at roomtemperature for 24 h. The reaction mixture is filtered, the residue isevaporated and the residue is purified by means of preparative HPLC;yield: 333 mg; HPLC: Rt=3.45 min; LC-MS: 552 (M+H).

49.3 70 mg (0.127 mmol) of tert-butyl[3-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)propyl]carbamateare dissolved in 3 ml of dichloromethane, and 195 μl (2.54 mmol) oftrifluoroacetic acid are added. The reaction mixture is stirred at roomtemperature for 15 h and evaporated. The residue is digested withdiethyl ether and dried in vacuo; yield: 74 mg of “A285”; HPLC: Rt=2.63min (method C); LC-MS: 452 (M+H).

EXAMPLE 50

Preparation of2-{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“A286”)

50.1 Preparation of methyl 3-(5-aminopyrimidin-2-yl)benzoate

65.4 g (274 mmol) of methyl 3-carbamimidoylbenzoate is suspended in 800ml of methanol, and 134 g (274 mmol) of({2-dimethylamino-1-[dimethylimmoniomethyl]vinylamino}methylene)dimethylammoniumdihexafluorophosphate are added. 102 ml (548 mmol) of 30% sodiummethoxide solution in methanol is added dropwise to this suspension. Asolution forms. This is stirred at an internal temperature of 60° C. for1 hour. After cooling to room temperature, a further 20 ml of 30% sodiummethoxide solution in methanol are added dropwise, and the mixture isstirred at 60° C. for 1 hour. After cooling to room temperature, theresultant precipitate is filtered off with suction, and the residue issuspended in 1 l of water and stirred at room temperature for 30 min.The precipitate is filtered off with suction and dried at 80° C. in avacuum drying cabinet; yield: 68.5 g; HPLC: Rt=2.03 min (method C);LC-MS: 285 (_(M+H)).

10.2 g (35.9 mmol) of methyl3-[5-(dimethylaminomethyleneamino)pyrimidin-2-yl]benzoate are suspendedin 1 l of methanol. 5.3 ml (107.3 mmol) of fuming sulfuric acid areadded dropwise with gentle cooling (about 5-10° C.) (note, highlyexothermic reaction). When the addition is complete, the mixture isstirred firstly at RT for 30 min and subsequently at an oil-bathtemperature of 88°. The reaction is monitored by means of HPLC. After 20h, the clear, dark-yellow solution is evaporated to dryness. The residueis dissolved in 600 ml of ethyl acetate and washed with 2×150 ml of 1 NNaOH and 2×1 N HCl, dried over sodium sulfate and evaporated; yield: 3g; HPLC: Rt=2.17 min (method C); LC-MS: 300 (M+H).

50.2 Preparation of{3-[5-(4-methylpiperazin-1yl)pyrimidin-2-yl]-phenyl}methanol

2.5 g (10.9 mmol) of methyl 3-(5-aminopyrimidin-2-yl)benzoate aredissolved in 10 ml of NMP, and 2.59 g (18.5 mmol) of potassium carbonateand 3.6 g (18.5 mmol ) of bis (2-chloroethyl)ethylamine hydrochlorideare added. The suspension is stirred at 120° C. for 15 h under an argonatmosphere. The mixture is subsequently stirred at 140° C. for a further12 h. After cooling to room temperature, the reaction mixture is stirredinto 150 ml of water. The resultant precipitate is filtered off throughkieselguhr with suction and discarded. The filtrate is adjusted to pH=14using 32% NaOH. The slightly cloudy solution is extracted with 2×200 mlof ethyl acetate. The combined organic phases are washed with saturatedsodium chloride solution, dried over sodium sulfate and evaporated todryness and dried in vacuo. The product is reacted further withoutfurther purification; yield: 860 mg; HPLC: Rt=2.11 min (method C);LC-MS: 313 (M+H).

860 mg (2.75 mmol) of methyl3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]-benzoate are dissolved in16 ml of THF, and 13.8 ml (13.8 mmol) of 1 M diisobutylaluminium hydridein THF are added dropwise at room temperature, and the reaction mixtureis stirred at room temperature for 1 h. A further 13.8 ml (13.8 mmol) of1 M diisobutylaluminium hydride in THF are added dropwise, and thereaction mixture is stirred at room temperature for 1 h. 3 ml ofsaturated sodium sulfate solution are added to the reaction mixture withice cooling. Dichloromethane is added to the gelatinous mixture, whichis then stirred for 30 min and filtered. The filtrate is dried oversodium sulfate and evaporated.

Yield: 300 mg, yellow solid. The product is reacted further withoutfurther purification; HPLC: 1.68 min (method C); LC-MS: 285 (M+H).

71 mg (0.40 mmol) of 6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one and163 mg (0.40 mmol) of{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]phenyl}-methanol aresuspended in 3 ml of THF and 1 ml of DMF with 200 mg (0.60 mmol) ofpolymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine perg) and shaken at room temperature for 30 min. 139 mg (0.60 mmol) ofdi-tert-butyl azodicarboxylate are added. The reaction mixture is shakenat room temperature for 1 h. A further 200 mg (0.6 mmol) ofpolymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine perg) and 139 mg (0.60 mmol) of di-tert-butyl azodicarboxylate are added,and the reaction mixture is shaken at room temperature for 2 h. Thereaction mixture is filtered, the residue is evaporated, and the residueis purified by means of preparative HPLC; yield: 18 mg of “A286”; HPLC:Rt=2.08 min (method C); LC-MS: 443 (M+H).

EXAMPLE 51

Preparation of3-(1-{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“A287”)

149 mg (0.76 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrileand 256 mg (0.76 mmol) of{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]phenyl}-methanol aresuspended in 5 ml of DMF with 378 mg (1.13 mmol) of polymer-boundtriphenylphosphine (about 3 mmol of triphenylphosphine per g) and shakenat room temperature for 30 min. 266 mg (1.134 mmol) of di-tert-butylazodicarboxylate are added. The reaction mixture is shaken at roomtemperature for 2 h. A further 378 mg (1.13 mmol) of polymer-boundtriphenylphosphine (about 3 mmol of triphenylphosphine per g) and 266 mg(1.134 mmol) of di-tert-butyl azodicarboxylate are added, and thereaction mixture is shaken at room temperature for 2 h. The reactionmixture is filtered, the filtrate is evaporated, and the residue ispurified by means of column chromatography on silica gel; yield: 59 mgof “A287”; HPLC: Rt=2.38 min (method C); LC-MS: 464 (M+H).

EXAMPLE 52

Preparation of3-{6-oxo-1-[3-(5-piperazin-1-ylpyrimidin-2-yl)benzyl]-1,6-dihydropyridazin-3-yl}benzonitrile(“A288”)

52.1 Preparation of tert-butyl4-[2-(3-hydroxymethylphenyl)pyrimidin-5-yl]piperazine-1-carboxylate

3.2 g (13.95 mmol) of methyl 3-(5-aminopyrimidin-2-yl)benzoate aredissolved in 80 ml of NMP, and 4.73 g (25.96 mmol) ofbis(2-chloroethyl)ammonium chloride and 3.13 g (23.73 mmol) of potassiumcarbonate are added. The suspension is stirred at 130° C. for 7 daysunder an argon atmosphere. The reaction mixture is filtered, and thefiltrate is stirred into 1 l of diethyl ether. An oily residue depositsin the process. The organic phase is separated off and discarded. 500 mlof ethyl acetate and 200 ml of saturated sodium hydrogencarbonatesolution are added to the residue, the organic phase is separated off,and the aqueous phase is extracted again with 500 ml of ethyl acetate.The organic phases are combined, dried over sodium sulfate andevaporated. The residue is reacted further without further work-up;yield: 2.4 g; HPLC: Rt=2.07 min (method C); LC-MS: 299 (M+H).

2.4 g (5.4 mmol) of methyl 3-(5-piperazin-1-ylpyrimidin-2-yl)benzoate isdissolved in 15 ml of DMF, 2.98 g (21.6 mmol) of potassium carbonate and1.5 ml (7.0 mmol) of di-tert-butyl dicarbonate are added, and themixture is stirred at room temperature for 30 min. The reaction mixtureis filtered, and the filtrate is evaporated. The residue is taken up in200 ml of ethyl acetate and 50 ml of saturated sodium hydrogencarbonatesolution. The organic phase is separated off and washed with 50 ml of 1N HCl, dried over sodium sulfate and evaporated. The product is reactedfurther without further purification; yield: 1.1 g; HPLC: 3.18 min(method C); LC-MS: 399 (M+H).

862 mg (2.16 mmol) of tert-butyl4-[2-(3-methoxycarbonylphenyl)pyrimidin-5-yl]piperazine-1-carboxylateare dissolved in 15 ml of THF, and 10.8 ml (10.8 mmol) of 1 Mdiisobutylaluminium hydride in THF are added at room temperature. Thereaction mixture is stirred at room temperature for 1 h. 3 ml of sat.sodium sulfate solution are added to the reaction mixture with icecooling. 30 ml of dichloromethane and 5 ml of methanol are added to thegelatinous mixture, which is then stirred for 10 min and filteredthrough kieselguhr with suction. The filtrate is dried over sodiumsulfate and evaporated. The residue is dissolved in dichloromethane andfiltered, and the filtrate is evaporated. The product is reacted furtherwithout further purification; yield: 677 mg; HPLC: 2.66 min (method C);LC-MS: 371 (M+H).

52.2

94 mg (0.48 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile and177 mg (0.48 mmol) of tert-butyl4-[2-(3-hydroxymethylphenyl)pyrimidin-5-yl]piperazine-1-carboxylate aresuspended in 4 ml of THF and 1 ml of DMF with 240 mg (0.72 mmol) ofpolymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine perg) and shaken at room temperature for 30 min. 168 mg (0.72 mmol) ofdi-tert-butyl azodicarboxylate are added. The reaction mixture isfiltered, the filtrate is evaporated, and the residue is purified bymeans of column chromatography on silica gel; yield: 143 mg; HPLC:Rt=3.24 min (method C); LC-MS: 550 (M+H).

143 mg (0.26 mmol of tert-butyl4-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)piperazine-1-carbamateare dissolved in 6 ml of acetonitrile, and 6 ml of 4 M HCl in dioxaneare added. The reaction mixture is stirred at room temperature for 1 hand evaporated. The residue is taken up in water and ethyl acetate, andthe water phase is adjusted to pH 12 using NaOH and extracted with ethylacetate and dichloromethane. The organic phases are combined, dried oversodium sulfate and purified by means of column chromatography.

Yield: 117 mg of “A288” HPLC: Rt=2.36 min (method C); LC-MS: 450 (M+H).

Preparation of a Precursor for the Preparation of “A289” and “A290”

1. Preparation of [3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methanol

3.46 g of methyl 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate (15.86 mmol)are dissolved in 50 ml of abs. THF in a 250 ml three-necked flask, and0.691 g of LiBH4 (31.71 mmol) is subsequently introduced in portionswith stirring at 0° C. under a nitrogen atmosphere, and the mixture isstirred without cooling for a further 20 h. For work-up, the reactionmixture is adjusted to pH 7 by slow dropwise addition of 1 N HCl withstirring, diluted with 100 ml of water and extracted 3× with 50 ml ofdichloromethane. The combined organic phases are washed 1× 100 ml ofwater, dried over sodium sulfate and evaporated to dryness in a rotaryevaporator. The purification is carried out by chromatography (50 g ofsilica gel/DCM+0-1% of MeOH). The product is crystallised from diethylether/petroleum ether; m.p. 57-58° C.

2. Preparation of 3-hydroxymethylbenzamidinium acetate

40 g of Raney nickel (water-wet) are added to 124.84 g of[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methanol (569.39 mmol) in amixture of 1300 ml of methanol, 100 ml of glacial acetic acid and 100 mlof water, and the mixture is hydrogenated at room temperature andatmospheric pressure until 14.7 I of hydrogen have been taken up (45 h).For work-up, the catalyst is filtered off, and the solution whichremains is evaporated to dryness, and the residue is boiled up in methyltert-butyl ether and filtered off. The crystals are dried overnight invacuo.

3. Preparation ofN′-[2-(3-hydroxymethylphenyl)pyrimidin-5-yl]-N,N-dimethylformamidine

716 mg of 3-hydroxymethylbenzamidinium acetate (3.41 mmol) and 1.66 g of({2-dimethylamino-1-[dimethylimmoniomethyl]vinylamino}methylene)-dimethylammoniumdihexafluorophosphate (amino-reduction precursor) (3.41 mmol) weresuspended in 15 ml of abs. methanol in an N₂-flushed 100 ml three-neckedflask with CaCl₂ protection, and a freshly prepared solution of 0.235 gof Na in 5 ml of abs. methanol is added dropwise with stirring. Thereaction mixture is stirred at 60° C. for 30 min, during which a clearsolution forms. For work-up, the reaction batch is diluted with 50 ml ofdichloromethane, washed 2× with 20 ml of water, evaporated to drynessand purified by chromatography (silica gel DCM+0-5% of MeOH); m.p.105-6° C.

EXAMPLE 53

Preparation of6-(4-methanesulfonylphenyl)-2-[3-(5-piperazin-1-yl-pyrimidin-2-yl)benzyl]-2H-pyridazin-3-one(“A289”)

53.1 1.95 g (7.8 mmol) of 6-(4-methanesulfonylphenyl)-2H-pyridazin-3-oneand 2 g (7.8 mmol) ofN′-[2-(3-hydroxymethylphenyl)pyrimidin-5-yl]-N,N-dimethylformamidine aresuspended in 50 ml of THF and 15 ml of DMF with 3.9 g (11.7 mmol) ofpolymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine perg) and shaken at room temperature for 30 min. 2.75 g (11.7 mmol) ofdi-tert-butyl azodicarboxylate are added.

The reaction mixture is shaken at room temperature for 15 h. A further2.6 g (7.8 mmol) of polymer-bound triphenylphosphine (about 3 mmol oftriphenylphosphine per g) and 1.80 g (7.8 mmol) of di-tert-butylazodicarboxylate are added. The reaction mixture is shaken at roomtemperature for 15 h. The reaction mixture is filtered, and the filtrateis evaporated. 1 N HCl (100 ml) is added to the oily residue, which isthen extracted with ethyl acetate (100 ml). The acidic water phase iswashed again with ethyl acetate and then adjusted to pH7 using solidsodium hydrogencarbonate. The mixture is extracted 2× with ethylacetate. The organic phase is evaporated, and the residue is dried invacuo; yield: 1 g; HPLC: Rt=2.19 min (method C); LC-MS: 489 (M+H).

53.2 1.7 g (3.48 mmol) ofN′-(2-{3-[3-(4-methanesulfonylphenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)-N,N-dimethylformamidineare dissolved in 30 ml of dioxane and 30 ml of water, and 1.68 g (12.2mmol) of potassium carbonate are added. The reaction mixture is refluxedfor 15 h. After cooling to room temperature, the reaction mixture isconcentrated to about 30 ml, and the resultant precipitate is filteredoff with suction, washed with water and dried in vacuo.

Yield: 1.5 g HPLC: 2.30 min (method C); LC-MS: 434 (M+H).

53.3 1.4 g (3.23 mmol) of2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(4-methanesulfonylphenyl)-2H-pyridazin-3-oneare dissolved in 30 ml of NMP, and 1.59 g (8.72 mmol) ofbis(2-chloroethyl)ethylamine hydrochloride and 1.22 g (8.72 mmol) ofpotassium carbonate are added. The suspension is stirred at 130° C. for5 days under an argon atmosphere. The reaction mixture is filtered, andthe filtrate is stirred into 200 ml of diethyl ether. An oily residuedeposits in the process. The residue is purified by means of columnchromatography on silica gel. The resultant product is purified by meansof preparative HPLC; yield: 41 mg of “A289” trifluoroacetate; HPLC:Rt=2.19 min (method C); LC-MS: 503 (M+H).

EXAMPLE 54

Preparation of4-{1-[3-(5-aminopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile(“A290”)

54.1 1.5 g (7.8 mmol) of 6-(4-cyanophenyl)-2H-pyridazin-3-one and 2 g(7.8 mmol) ofN′-[2-(3-hydroxymethylphenyl)pyrimidin-5-yl]-N,N-dimethylformamidine aresuspended in 50 ml of THF and 15 ml of DMF with 3.9 g (11.7 mmol) ofpolymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine perg) and shaken at room temperature for 30 min. 2.75 g (11.7 mmol) ofdi-tert-butyl azodicarboxylate are added. The reaction mixture is shakenat room temperature for 15 h. A further 2.6 g (7.8 mmol) ofpolymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine perg) and 1.80 g (7.8 mmol) of di-tert-butyl azodicarboxylate are added.The reaction mixture is shaken at room temperature for 15 h. Thereaction mixture is filtered, and the filtrate is evaporated. 1 N HCl(100 ml) is added to the oily residue, which is then extracted withethyl acetate (100 ml). The acidic water phase is washed again withethyl acetate and then adjusted to pH7 using solid sodiumhydrogencarbonate. The mixture is extracted 2× with ethyl acetate. Theorganic phase is evaporated, and the residue is dried in vacuo; yield:1.2 g; HPLC: Rt=1.59 min (method C); LC-MS: 436 (M+H).

54.2 1.2 g (3.48 mmol) ofN′-(2-{3-[3-(4-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)-N,N-dimethylformamidineare dissolved in 50 ml of dioxane and 50 ml of water, and 1.2 g (8.7mmol) of potassium carbonate are added. The reaction mixture is refluxedfor 15 h. After cooling to room temperature, the reaction mixture isconcentrated to about 30 ml, and the resultant precipitate is filteredoff with suction, washed with water and dried in vacuo. The residue ispurified by means of column chromatography on silica gel; yield: 145 mgof “A290”; HPLC: 2.49 min (method C); LC-MS: 381 (M+H).

The compound3-{1-[3-(5-aminopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile(“A291”); ESI 381, is obtained analogously.

EXAMPLE 55

Preparation of

6-(1-methyl-1H-pyrazol-4-yl)-2-[3-(5-piperazin-1-ylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one(“A292”) and

2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“A293”)

55.1 Preparation ofN,N-dimethyl-N′-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)formamidine

3.33 g (24.1 mmol) of potassium carbonate are added to a solution of 1.7g (4.8 mmol) of 6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one and 1.22g (4.8 mmol) of 3-(3-bromomethylphenyl)-5-methyl-1,2,4-oxadiazole(prepared by the method of W. W. K. R. Mederski et al, Tetrahedron 55,1999, 12757-12770) in 50 ml of DMF, and the resultant suspension isstirred at room temperature for 5 days. Water is added to the reactionmixture, which is then extracted with ethyl acetate. The organic phaseis washed with water, dried over sodium sulfate and evaporated.Isopropanol is added to the residue, and the mixture is stirred for 15min and filtered, and the residue is rinsed with isopropanol and diethylether and dried in vacuo.

Yield: 740 mg; HPLC: Rt=2.42 min (method C); LC-MS: 349 (M+H).

2 ml of acetic acid, 2 ml of water and 6 g of Raney nickel are added toa solution of 6.77 g (19.4 mmol) of6-(1-methyl-1H-pyrazol-4-yl)-2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2H-pyridazin-3-onein 300 ml of methanol, and the mixture is hydrogenated at roomtemperature and under a hydrogen atmosphere for 2 days. The reactionmixture is filtered, and the filtrate is evaporated and dried in vacuo.The product was reacted further without further purification; yield: 6g; HPLC: 1.74 min (method C); LC-MS: 309 (M+H).

A suspension of 7.5 g (20.4 mmol) of3-[6-oxo-3-(1-methyl-1H-pyrazol-4-yl)-6H-pyridazin-1-ylmethyl]benzamidiniumacetate and 9.94 g (20.4 mmol) of({2-dimethylamino-1-[dimethylimmoniomethyl]vinylamino}methylene)dimethylammoniumdihexafluorophosphate are dissolved in 70 ml of methanol, and 7.6 ml(40.7 mmol) of 30% sodium methoxide solution in methanol are addeddropwise. The reaction mixture is slowly warmed to 60° C. and stirred atthis temperature for 60 minutes. After the mixture has been cooled toroom temperature, a further 5.6 ml (30.0 mmol) of 30% sodium methoxidesolution in methanol are added dropwise, and the mixture is stirred at60° C. for 2 h. After cooling, the solvent is removed by distillation,and water is added to the residue. The aqueous phase is decanted off,ethyl acetate is added to the residue, and the mixture is stirred atroom temperature for 15 min. The precipitate is filtered off withsuction, washed with ethyl acetate and dried in vacuo; yield: 6.8 g ofbeige solid; HPLC: 2.05 min (method C); LC-MS: 415 (M+H).

55.2

130 ml of dioxane and 5 g (11.4 mmol) ofN,N-dimethyl-N′-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)formamidineare added to a solution of 5.5 g (40 mmol) of potassium carbonate in 130ml of water. The reaction mixture is heated at the boil for 15 h andsubsequently cooled to room temperature. The dioxane is removed bydistillation, and the resultant precipitate is filtered off withsuction, washed with water and dried in vacuo; yield: 3.6 g of “A293”;HPLC: 2.11 min (method C); LC-MS: 360 (M+H).

1.4 g (7.5 mmol) of bis(2-chloroethyl)methylammonium chloride are addedto a solution, kept under nitrogen, of 1 g (2.78 mmol) of2-[3-(5-amino-pyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“A293”) in 25 ml of 1-methylpyrrolidone, and the reaction mixture isheated at 130° C. for 5 days. The reaction mixture is cooled andfiltered, and the filtrate is added to 200 ml of diethyl ether. An oilyresidue deposits, to which 100 ml of saturated sodium hydrogencarbonatesolution are added, and the mixture is extracted with 3×150 ml ofdichloromethane. The organic phases are dried over sodium sulfate andevaporated. 300 mg of this residue are dissolved in 5 ml of DMF, and 387mg of potassium carbonate and 195 μl (0.91 mmol) of di-tert-butyldicarbonate are added, and the mixture is stirred at room temperaturefor 1 h. The reaction mixture is filtered, and the filtrate isevaporated. The residue is suspended in dichloromethane and washed withsaturated sodium hydrogencarbonate. The organic phase is dried oversodium sulfate and subsequently evaporated. The residue is purified bymeans of column chromatography on silica gel; yield: 36 mg; HPLC: 2.89min (method C); LC-MS: 529 (M+H).

90 mg (0.17 mmol) of tert-butyl4-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)piperazine-1-carboxylateare dissolved in 10 ml of dioxane, and 1 ml of 4 N HCl in dioxane isadded. The reaction mixture is stirred at room temperature for 15 h andsubsequently evaporated to dryness; yield: 80 mg of “A292”hydrochloride; HPLC: 2.05 min (method C); LC-MS: 429 (M+H).

EXAMPLE 56

Alternative preparation of3-{1-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile(“A263”)

1. Preparation of3-{1-[3-(5-bromopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile

61.13 g of 3-cyanophenylpyridazinone (0.31 mol) and 87.9 g of5-bromo-2-(3-chloromethylphenyl)pyrimidine (0.31 mol) are dissolved in610 ml of DMF under an inert-gas atmosphere in a 1000 ml one-neckedflask, and 111.11 g of caesium carbonate (0.34 mol) are subsequentlyadded. The reaction mixture is stirred at 40° C. for 72 h. For work-up,the mixture is diluted with 600 ml of water with stirring, and theresultant precipitate is washed with copious water and a little methanoland chromatographed over 1 kg of silica gel. The product fractions arecombined and evaporated to dryness in a rotary evaporator, and theproduct is slurried with a little methanol, filtered off with suctionand dried at 70° C. in vacuo; m.p. 178-9° C.

2. Preparation of3-(6-oxo-1-{3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile

35.57 g of3-{1-[3-(5-bromopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile(0.08 mol), 26.43 g of bis(pinacolato)diboron (0.104 mol) and 23.75 g ofpotassium acetate (0.240 mol) are suspended in 165 ml of abs. DMF underan N₂ atmosphere in a 500 ml three-necked flask and heated at 70° C.with stirring, 1.686 g of (PPh₃)₂PdCl₂ (2.4 mmol) are subsequentlyadded, and the reaction batch is stirred at 70° C. for 6 h, during whicha dark-brown solution forms. For work-up, the reaction mixture isdiluted with 600 ml of water with stirring at RT, and the resultantprecipitate is filtered off with suction. The resultant precipitate istaken up in 500 ml of dichloromethane, shaken 2× with 200 ml of water,dried over sodium sulfate and evaporated to dryness. The residue isslurried in 200 ml of acetone, filtered off with suction and washed witha little acetone, m.p. 203-5° C.

3. Preparation of3-{1-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile(“A263”)

50.46 g of3-(6-oxo-1-{3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile(102.7 mmol) and 33.81 g of sodium perborate tetrahydrate (339 mmol) aremixed in a mixture of 220 ml of THF and 220 ml of water in a 1000 mlone-necked flask and stirred at room temperature for 2 h, during which apale precipitate deposits. The reaction mixture is diluted with 800 mlof dichloromethane, shaken with 500 ml of saturated aqueous ammoniumchloride solution, dried over sodium sulfate and evaporated to drynessin a rotary evaporator. The residue is slurried in methanol, filteredoff with suction and washed with diethyl ether, m.p. 245-8° C.

EXAMPLE 57

Preparation of2-{3-[5-(2-hydroxyethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“A294”)

252 mg of2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(0.7 mmol) are suspended in abs. THF under a protective-gas atmospherein a 25 ml three-necked flask, 0.19 ml of2-(tetrahydropyran-2-yloxy)ethanol (1.4 mmol) and 367 mg oftriphenylphosphine (1.4 mmol) are added, and the mixture is stirred atRT for 30 min. 275 μl of diisopropyl azodicarboxylate (1.4 mmol) aresubsequently added dropwise, and the reaction mixture is stirred at RTfor a further 2 h. For work-up, the reaction mixture is diluted with 20ml of dichloromethane, washed with 10 ml of water, dried over sodiumsulfate, evaporated to dryness and purified by chromatography. (silicagel: MTB ether→DCM→DCM:30% of MeOH). The THP-protected product isstirred at RT for 20 h in 5 ml of 4 N HCl in dioxane. The reactionsolution is evaporated to dryness and crystallised from methanol/diethylether, giving “A294”; ESI 405; m.p. 182-3° C.

The following compounds are obtained analogously

Compound ESI No. Name and/or structure [M + H]⁺ “A295”3-(1-{3-[5-(3-hydroxypropoxy)pyrimidin- 4402-yl]benzyl}-6-oxo-1,6-dihydropyridazin- 3-yl)benzonitrile “A296”3-(1-{3-[5-(2-hydroxyethoxy)pyrimidin- 4262-yl]benzyl}-6-oxo-1,6-dihydropyridazin- 3-yl)benzonitrile “A297”2-{3-[5-(3-hydroxypropoxy)pyrimidin- 4192-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)- 2H-pyridazin-3-one

EXAMPLE 58

Preparation of1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}-ethanol(precursor of “A298”)

1. Preparation of ethyl 3-acetylbenzimidinate

30 g of 3-cyanacetophenone (207 mmol) are suspended in 170 ml of a 10%solution of HCl in diethyl ether in a 500 ml one-necked flask and cooledto 0° C., and 18.68 ml of abs. ethanol are added. The reaction mixtureis stirred at RT for 14 days. For work-up, the reaction mixture isdiluted with 500 ml of diethyl ether, the precipitate is filtered offwith suction and rinsed with copious diethyl ether, and the residue isdried at 50° C. in a vacuum drying cabinet; m.p. 122-4° C.

2. Preparation of 3-acetylbenzamidine

17.453 g of ethyl 3-acetylbenzimidinate are suspended in 190 ml of abs.ethanol in a 1000 ml one-necked flask, and 190 ml of a 10% solution ofammonia in ethanol are subsequently added, and the reaction batch isrefluxed for 3 h. The reaction batch is evaporated to dryness in arotary evaporator and employed in crude form in the next step; LC-MS:0.886 min/M+H⁺: 163.2 g/mol.

3. Preparation ofN′-[2-(3-acetylphenyl)pyrimidin-5-yl]-N,N-dimethylformamidine

16.18 g of 3-acetylbenzamidine (content 77%) (76.62 mmol) and 37.41 g of({2-dimethylamino-1-[dimethylimmoniomethyl]vinylamino}methylene)dimethylammoniumdihexafluorophosphate (amino-reduction precursor) (76.62 mmol) aresuspended in 200 ml of abs. methanol in an N₂-flushed 1000 mlthree-necked flask with CaCl₂ protection, and a freshly prepared 1.5 Msodium methoxide solution in methanol is added dropwise with stirring.The reaction mixture is stirred at 60° C. for 30 min, during which aclear solution forms. For work-up, about 90% of the methanol are removedin a rotary evaporator, and the remaining residue is diluted with 300 mlof dichloromethane, washed 2× with 100 ml of water, dried over sodiumsulfate and evaporated to dryness. The purification is carried out bychromatography (silica gel DCM +1-5% of MeOH). The product fractions arecombined, evaporated to dryness and stirred with i-PrOH; m.p. 146-8° C.

4. Preparation of 1-[3-(5-hydroxypyrimidin-2-yl)phenyl]ethanone

5.10 g of N′-[2-(3-acetylphenyl)pyrimidin-5-yl]-N,N-dimethylformamidine(19 mmol) are suspended in 65 ml of water in a 250 ml one-necked flaskprovided with magnetic stirrer and condenser, 8.44 ml of 95-97% sulfuricacid (152 mmol) are added, and the mixture is stirred at a bathtemperature of 130° C. for 2 h. The mixture is diluted with ice-water,during which a dark-brown resin deposits. The aqueous solution isdecanted off and extracted with dichloromethane. The combineddichloromethane phases are dried, filtered and evaporated to dryness,and the residue is triturated with ether, filtered off with suction anddried (=K1). The deposited dark-brown resin is extracted by stirringwith tetrahydrofuran, filtered off with suction, the crystals arediscarded, and the mother liquor is evaporated to dryness (=R1). Theaqueous phase from the dichloromethane extraction is evaporated todryness, the residue is extracted by stirring 2× with tetrahydrofuran,and the combined decanted-off solutions are diluted withdichloromethane, dried, filtered and evaporated to dryness (=R2). R1 andR2 are combined, adsorbed on silica gel and purified by chromatography(silica gel/dichloromethane+0-5% of methanol). The chromatographyresidue is triturated with ether, filtered off with suction, washed withether and dried (=K2).

K1 and K2 are combined; m.p. 199-200° C.

5. Preparation of1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]-phenyl}ethanone

2.4 g of 1-[3-(5-hydroxypyrimidin-2-yl)phenyl]ethanone (11.2 mmol) aresuspended in 40 ml of abs. THF in an N₂-flushed apparatus with CaCl₂protection, 1.576 ml of 3-(dimethylamino)-1-propanol (13.44 mmol) and5.602 g of polymer-bound triphenylphosphine (16.81 mmol) are added, andthe mixture is stirred at RT for 30 min. 3.87 g of di-tert-butylazodicarboxylate (16.81 mmol) are added with ice/H₂O cooling andstirring, and the mixture is stirred at RT for a further 2 h. Forwork-up, the polymer is removed by filtration and rinsed with copiousdichloromethane, and the filtrate is extracted 1× with water and 2× withaqueous 1 N HCl. The combined HCl extracts are rendered alkaline usingNaOH and extracted 3× with 50 ml of dichloromethane. The dichloromethaneextracts are combined, dried over sodium sulfate, evaporated to drynessand crystallised from petroleum ether 40-60; m.p. 61-2° C.

6. Preparation of1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]-phenyl}ethanol

3.114 g of1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}ethanone (10.4mmol) are dissolved in 30 ml of abs. ethanol in a 100 ml one-neckedflask, and 0.394 g of sodium borohydride (10.4 mmol) is subsequentlyadded in portions with ice/water cooling and stirring, and the reactionbatch is stirred at RT for a further 20 h. For work-up, the reactionmixture is diluted with 50 ml of dichloromethane and shaken 2× againstwater, and the dichloromethane phase is evaporated to dryness andpurified by chromatography (silica gel/DCM/MeOH 9:1);

HPLC: RT: 2.40 min;

LC-MS: 1.330 min/M+H⁺: 302.2 g/mol.

EXAMPLE 59

Preparation of3-[1-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]-phenyl}ethyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile(“A298”)

197 mg of 3-cyanophenylpyridazinone (1.00 mmol) is suspended in amixture of 5 ml of abs. THF and 1 ml of abs. DMF in an N₂-flushedapparatus with CaCl₂ protection, 301 mg of1-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]phenyl}ethanol (1.00mmol) and 500 mg of polymer-bound triphenylphosphine (1.5 mmol) areadded, the mixture is stirred at RT for 30 min, 345 mg of di-tert-butylazodicarboxylate (1.5 mmol) are subsequently added with ice/H₂O coolingand stirring, and the mixture is stirred at RT for a further 2 h. Forwork-up, the reaction mixture is diluted with 10 ml of methanol, and thepolymer is removed by filtration. The residue is washed withdichloromethane, and the combined filtrate is evaporated to dryness in arotary evaporator and purified by chromatography (silica gel: DCM+0-30%of MeOHF), giving “A298”, m.p. 105-7° C.

The following compounds are obtained analogously

Compound ESI No. Name and/or structure [M + H]⁺ “A299”6-(3,5-difluorophenyl)-2-(1-{3-[5- 492(3-dimethylamino-propoxy)pyrimidin-2-yl]phenyl}ethyl)-2H-pyridazin-3-one “A300”6-(3,5-difluorophenyl)-2-((R)-1-{3-[5- 492(3-dimethylamino-propoxy)pyrimidin-2- yl]phenyl}ethyl)-2H-pyridazin-3-one, hydrochloride “A301” 6-(3,5-difluorophenyl)-2-((S)-1-{3-[5- 492(3-dimethylamino-propoxy)pyrimidin-2- yl]phenyl}ethyl)-2H-pyridazin-3-one, hydrochloride

EXAMPLE 60

Preparation of3-(1-{3-[5-(1-methyl-1-oxypiperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“A302”)

100 mg of3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(0.203 mmol) are suspended in 5 ml of water and 5 ml of acetonitrile ina reaction vial provided with a magnetic stirrer, 100 μl of perhydrol(0.979 mmol) are added, and the mixture is stirred at RT for 24 h. Themixture is then poured into water and extracted with dichloromethane,and the combined dichloromethane phases are dried, filtered andevaporated to dryness. The residue is adsorbed on silica gel andchromatographed (dichloromethane+0-50% of methanol). The chromatographyresidue is freeze-dried; ESI 509; m.p. 85° C. (decomposition).

EXAMPLE 61

Preparation of3-(1-{3-[5-(1-formylpiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile,ESI 409:

EXAMPLE 62

Reaction of3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-1,6-dihydropyridazin-3-yl)benzonitrilewith dimethylaminoethyl chloride hydrochloride and caesium carbonate inDMF followed by chromatographic separation gives

EXAMPLE 63

Reaction of3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-1,6-dihydropyridazin-3-yl)benzonitrilewith beta-bromoethyl methyl ether and caesium carbonate in DMF gives thecompound

EXAMPLE 64

Reaction of3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-1,6-dihydropyridazin-3-yl)benzonitrilewith bromoethane and caesium carbonate in DMF gives the compound

Pharmacological Data

TABLE 1 Met kinase inhibition of some representative compounds of theformula I Compound IC₅₀ IC₅₀ No. (cell assay) (enzyme assay) “A1” A A“A2” A A “A6” A “A8” A “A9” A “A13” B “A14” A “A15” A “A16” A “A17” A“A18” A “A19” A “A20” A “A22” A “A23” A “A25” A “A26” A “A35” A “A57” A“A63” A “A64” A “A66” A “A79” A “A102” A “A168” A “A169” A “A189” A“A209” A “A226” A “A229” A “A237” A “A257” A “A287” A “A288” A IC₅₀: 1nM-1 μM = A 1 μM-10 μM = B >10 μM = C

The compounds shown in Table I are particularly preferred compoundsaccording to the invention.

The following examples relate to medicaments:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

The invention claimed is:
 1. A compound of formula I

in which R¹ denotes Ar or Het, R² denotes pyrimidinyl, which isunsubstituted or mono-, di- or trisubstituted by Hal, A,[C(R³)₂]_(n)OR³, N═CR³N(R³)₂, SR³, NO₂, CN, COOR³, CON(R³)₂, NR³COA,NR³SO₂A, SO₂N(R³)₂, S(O)_(m)A, [C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)Het,O[C(R³)₂]_(p)OR³, O[C(R³)₂]_(n)N(R³)₂,O[C(R³)₂]_(n)C≡C[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)N⁺O³¹ (R³)₂,O[C(R³)₂]_(n)Het, S[C(R³)₂]_(n)N(R³)₂, S[C(R³)₂]_(n)Het,NR³[C(R³)₂]_(n)N(R³)₂, NR³[C(R³)₂]_(n)Het, NHCON(R³)₂,NHCONH[C(R³)₂]_(n)N(R³)₂, NHCONH[C(R³)₂]_(n)Het,[C(R³)₂]_(n)NHCO[C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)NHCO[C(R³)₂]_(n)Het,CON(R³)₂, CONR³[C(R³)₂]_(n)N(R³)₂, CONR³[C(R³)₂]_(n)NR³COOA,CONR³[C(R³)₂]_(n)OR³, CONR³[C(R³)₂]_(n)Het, COHet, COA, CH═CH—COOR³,CH═CH—N(R³)₂ and/or ═O, R³ denotes H or A, R⁴, R^(4′) each,independently of one another, denote H, Hal, A, OR³, CN, COOR³,CON(R³)₂, NR³COA, NR³SO₂A, SO₂N(R³)₂ or S(O)_(m)A, Ar denotes phenyl,naphthyl or biphenyl, each of which is unsubstituted or mono-, di- ortrisubstituted by Hal, A, [C(R³)₂]_(n)OR³, [C(R³)₂]_(n)N(R³)₂, SR³, NO₂,CN, COOR³, CON(R³)₂, NR³COA, NR³SO₂A, SO₂N(R³)₂, S(O)_(m)A, CO-Het, Het,O[C(R³)₂]_(n−)N(R³)₂, O[C(R³)₂]_(n)Het, NHCOOA, NHCON(R³)₂,NHCOO[C(R³)₂]_(n)N(R³)₂, NHCOO[C(R³)₂]_(n)Het, NHCONH[C(R³)₂]_(n)N(R³)₂,NHCONH[C(R³)₂]_(n)Het, OCONH[C(R³)₂]_(n)N(R³)₂, OCONH[C(R³)₂]_(n)Het,CONR³[C(R³)₂]_(n)N(R³)₂, CONR³[C(R³)₂]_(n)Het and/or COA, Het denotes amono-, bi- or tricyclic saturated, unsaturated or aromatic heterocyclehaving 1 to 4 N, O and/or S atoms, which is unsubstituted or mono-, di-,tri-, tetra- or penta- substituted by Hal, A, [C(R³)₂]_(n)OR³,[C(R³)₂]_(n)N(R³)₂, SR³, NO₂, CN, COOR³, CON(R³)₂, NR³COA, NR³SO₂A,SO₂N(R³)₂, S(O)_(m)A, CO-Het¹, [C(R³)₂]_(n)Het¹, O[C(R³)₂]_(n)N(R³)₂,O[C(R³)₂]_(n)Het¹, NHCOOA, NHCON(R³)₂, NHCOO[C(R³)₂]_(n)N(R³)₂,NHCOO[C(R³)₂]_(n)Het¹, NHCONH[C(R³)₂]_(n)N(R³)₂, NHCONH[C(R³)₂]_(n)Het¹,OCONH[C(R³)₂]_(n)N(R³)₂, OCONH[C(R³)₂]_(n)Het¹, CO-Het¹, CHO, COA, ═S,═NH, ═NA and/or ═O, and where a ring nitrogen is optionally oxidized,Het¹ denotes a monocyclic saturated heterocycle having 1 to 2 N and/or Oatoms, which is unsubstituted or mono- or disubstituted by A, OA, OH,Hal and/or ═O, A denotes unbranched or branched alkyl having 1-10 Catoms, in which 1-7 H atoms are optionally replaced by F and/or in whichone or two non-adjacent CH₂ groups are optionally replaced by O, NH, S,SO, SO₂ and/or by CH═CH groups, or cyclic alkyl having 3-7 C atoms, Haldenotes F, Cl, Br or I, m denotes 0, 1 or 2, n denotes 0, 1, 2, 3 or 4,and p denotes 1, 2, 3 or 4, or a pharmaceutically acceptable solvate,salt, tautomer or stereoisomer thereof.
 2. A compound according to claim1, in which R² denotes pyrimidines, which is monosubstituted by Hal, A,[C(R³)₂]_(n)OR³, N═CR³N(R³)₂, CN, COOR³, [C(R³)₂]_(n)N(R³)₂,[C(R³)₂]_(n)Het, O[C(R³)₂]_(p)OR³, O[C(R³)₂]_(n)N(R³)₂,O[C(R³)₂]_(n)C≡C[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)N⁺O⁻(R³)₂,O[C(R³)₂],_(n)Het, NR³[C(R³)₂]_(n)N(R³)₂, NR³[C(R³)₂]_(n)Het,[C(R³)₂]_(n)NHCO[C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)NHCO[C(R³)₂]_(n)Het,CONR³[C(R³)₂]_(n)N(R³)₂, CONR³[C(R³)₂]_(n)NR³COOA, CONR³[C(R³)₂]_(n)OR³,CONR³[C(R³)₂]_(n)Het, COHet, CH═CH—COOR³, CH═CH—N(R³)₂ and/or ═O, or apharmaceutically acceptable solvate, salt, tautomer or stereoisomerthereof.
 3. A compound according to claim 1, in which Ar denotes phenyl,naphthyl or biphenyl, each of which is unsubstituted or mono-, di- ortrisubstituted by A, Hal, CN, S(O)_(m)A, NR³COA, CON(R³)₂,O[C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)OR³, CONR³[C(R³)₂]_(n)N(R³)₂ and/orCONR³[C(R³)₂]_(n)Het, or a pharmaceutically acceptable solvate, salt,tautomer or stereoisomer thereof.
 4. A compound according to claim 1, inwhich R⁴, R^(4′) denote H, or a pharmaceutically acceptable solvate,salt, tautomer or stereoisomer thereof.
 5. A compound according to claim1, in which Het denotes a mono-, bi- or tricyclic saturated, unsaturatedor aromatic heterocycle having 1 to 4 N, O and/or S atoms, which isunsubstituted or mono-, di-, tri-, tetra- or penta- substituted by A,CHO, COOR³, CON(R³)₂, [C(R³)₂]_(n)Het¹, [C(R³)₂]_(n)OR³,[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)Het¹ and/or ═O, and where a ringnitrogen is optionally oxidized, or a pharmaceutically acceptablesolvate, salt, tautomer or stereoisomer thereof.
 6. A compound accordingto claim 1, in which Het¹ denotes a monocyclic saturated heterocyclehaving 1 to 2 N and/or O atoms, which is unsubstituted or mono- ordisubstituted by A and/or ═O, or a pharmaceutically acceptable solvate,salt, tautomer or stereoisomer thereof.
 7. A compound according to claim1, in which A denotes unbranched or branched alkyl having 1-8 C atoms,in which 1-7 H atoms are optionally replaced by F, or a pharmaceuticallyacceptable solvate, salt, tautomer or stereoisomer thereof.
 8. Acompound according to claim 1, in which R¹ denotes Ar orbenzo-2,1,3-thiadiazolyl, or a pharmaceutically acceptable solvate,salt, tautomer or stereoisomer thereof.
 9. A compound according to claim1, in which R³ denotes H, methyl, ethyl or propyl, or a pharmaceuticallyacceptable solvate, salt, tautomer or stereoisomer thereof.
 10. Acompound according to claim 1, in which R² denotes pyrimidinyl, which isunsubstituted or mono-, di- or trisubstituted by Hal, A,[C(R³)₂]_(n)OR³, N═CR³N(R³)₂, CN, COOR³, [C(R³)₂]_(n)N(R³)₂,[C(R³)₂]_(n)Het, O[C(R³)₂]_(p)OR³, O[C(R³)₂]_(n)N(R³)₂,O[C(R³)₂]_(n)C≡C[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)N⁺O³¹ (R³)₂,O[C(R³)₂]_(n)Het, NR³[C(R³)₂]_(n)N(R³)₂, NR³[C(R³)₂]_(n)Het,[C(R³)₂]_(n)NHCO[C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)NHCO[C(R³)₂]_(n)Het,CONR³[C(R³)₂]_(n)N(R³)₂, CONR³[C(R³)₂]_(n)NR³COOA, CONR³[C(R³)₂]_(n)OR³,CONR³[C(R³)₂]_(n)Het, COHet, CH═CH—COOR³, CH═CH—N(R³)₂ and/or ═O, or apharmaceutically acceptable solvate, salt, tautomer or stereoisomerthereof.
 11. A compound according to claim 1, in which Het denotespiperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl,indolyl, benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl,azabicyclo[2.2.2]octyl, imidazolidinyl, azepanyl orbenzo-2,1,3-thiadiazolyl, each of which is unsubstituted or mono-, di-,tri-, tetra- or penta- substituted by A, CHO, COOR³, CON(R³)₂,[C(R³)₂]_(n)Het¹, [C(R³)₂]_(n)OR³, [C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)Het¹and/or ═O, and where a ring nitrogen is optionally oxidized, or apharmaceutically acceptable solvate, salt, tautomer or stereoisomerthereof.
 12. A compound according to claim 1, in which Het¹ denotespyrrolidine, piperidine, piperazine or morpholine, each of which isunsubstituted or mono- or disubstituted by A and/or ═O, or apharmaceutically acceptable solvate, salt, tautomer or stereoisomerthereof.
 13. A compound according to claim 1, in which R¹ denotes Ar orHet, R² denotes pyrimidinyl, which is unsubstituted or mono-, di- ortrisubstituted by Hal, A, [C(R³)₂]_(n)OR³, N═CR³N(R³)₂, CN, COOR³,[C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)Het, O[C(R³)₂]_(p)OR³,O[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)C≡C[C(R³)₂]_(n)N(R³)₂,O[C(R³)₂]_(n)N⁺O³¹ (R³)₂, O[C(R³)₂]_(n)Het, NR³[C(R³)₂]_(n)N(R³)₂,NR³[C(R³)₂]_(n)Het, [C(R³)₂]_(n)NHCO[C(R³)₂]_(n)N(R³)₂,[C(R³)₂]_(n)NHCO[C(R³)₂]_(n)Het, CONR³[C(R³)₂]_(n)N(R³)₂,CONR³[C(R³)₂]_(n)NR³COOA, CONR³[C(R³)₂]_(n)OR³, CONR³[C(R³)₂]_(n)Het,COHet, CH═CH—COOR³, CH═CH—N(R³)₂ and/or ═O, R³ denotes H, methyl, ethylor propyl, R⁴, R^(4′) denote H, Ar denotes phenyl, naphthyl or biphenyl,each of which is unsubstituted or mono-, di- or trisubstituted by A,Hal, CN, S(O)_(m)A, NR³COA, CON(R³)₂, O[C(R³)₂]_(n)N(R³)₂,[C(R³)₂]_(n)OR³, CONR³[C(R³)₂]_(n)N(R³)₂ and/or CONR³[C(R³)₂]_(n)Het,Het denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl,oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl,benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl,azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, imidazolidinyl, azepanylor benzo-2,1,3-thiadiazolyl, each of which is unsubstituted or mono-,di-, tri-, tetra- or penta- substituted by A, CHO, COOR³, CON(R³)₂,[C(R³)₂]_(n)Het¹, [C(R³)₂]_(n)OR³, [C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)Het¹and/or ═O, and where a ring nitrogen is optionally oxidized, Het¹denotes pyrrolidine, piperidine, piperazine or morpholine, each of whichis unsubstituted or mono- or disubstituted by A and/or ═O, A denotesunbranched or branched alkyl having 1-8 C atoms, in which 1-7 H atomsare optionally replaced by F, Hal denotes F, Cl, Br or I, m denotes 0, 1or 2, n denotes 0, 1, 2, 3 or 4, and p denotes 1, 2, 3 or 4, or apharmaceutically acceptable solvate, salt, tautomer or stereoisomerthereof.
 14. A process for preparing a compound of formula I accordingto claim 1 or a pharmaceutically acceptable solvate, salt, tautomer orstereoisomer thereof, comprising reacting a compound of formula II

in which R¹ has the meaning indicated for the compound of formula I,with a compound of formula III

in which R², R³, R⁴ and R^(4′) have the meanings indicated for thecompound of formula I and L denotes Cl, Br, I or a free or reactivelyfunctionally modified OH group, and/or converting a base or acidcompound of formula I into one of its salts.
 15. A pharmaceuticalcomposition, comprising at least one compound of formula I according toclaim 1 or a pharmaceutically acceptable solvate, salt, tautomer orstereoisomer thereof, and one or more pharmaceutically acceptableexcipients and/or adjuvants.
 16. A pharmaceutical composition accordingto claim 15, further comprising at least one further pharmaceuticallyactive ingredient.
 17. A kit, comprising separate packs of (a) acompound of formula I according to claim 1 or a pharmaceuticallyacceptable solvate, salt, tautomer or stereoisomer thereof, and (b) afurther pharmaceutically active ingredient.
 18. A process for preparinga compound of formula I according to claim 1 or a pharmaceuticallyacceptable salt, tautomer or stereoisomer thereof, comprising reacting acompound of formula II

in which R¹ has the meaning indicated for the compound of formula I,with a compound of formula III

in which R², R³, R⁴ and R^(4′) have the meanings indicated for thecompound of formula I and L denotes Cl, Br, I or a free or reactivelyfunctionally modified OH group.
 19. A compound according to claim 1,wherein R² is pyrimidinyl, which is monosubstituted by Hal, A,[C(R³)₂]_(n)OR³, N═CR³N(R³)₂, SR³, NO₂, CN, COOR³, CON(R³)₂, NR³COA,NR³SO₂A, SO₂N(R³)₂, S(O)_(m)A, [C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)Het,O[C(R³ ₂]_(p)OR³, O[C(R³)₂]_(n)N(R³)₂,O[C(R³)₂]_(n)C≡C[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)N⁺O⁻(R³)₂,O[C(R³)₂]_(n)Het, S[C(R³)₂]_(n)N(R³)₂S[C(R³)₂]_(n)Het,NR³[C(R³)₂]_(n)N(R³)₂, NR³[C(R³)₂]_(n)Het, NHCON(R³)₂,NHCONH[C(R³)₂]_(n)N(R³)₂, NHCONH[C(R³)₂]_(n)Het,[C(R³)₂]_(n)NHCO[C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)NHCO[C(R³)₂]_(n)Het,CON(R³)₂, CONR³[C(R³)₂]_(n)N(R³)₂, CONR³[C(R³)₂]_(n)NR³COOA,CONR³[C(R³)₂]_(n)OR³, CONR³[C(R³)₂]_(n)Het, COHet, COA, CH═CH—COOR³,CH═CH—N(R³)₂ and/or ═O.
 20. A compound, which is one of the followingcompounds No. Name and/or structure “A1”2-[3-(5-methylpyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one “A2”6-(3,5-difluorophenyl)-2-[3-(5-methylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one “A3”2-[3-(4-methylpyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one “A4”2-(3-pyrimidin-2-ylbenzyl)-6-(3,4,5-trifluorophenyl)-2H- pyridazin-3-one“A13” 6-(3,5-difluorophenyl)-2-[3-(4-piperazin-1-ylpyrimidin-2-yl)-benzyl]-2H-pyridazin-3-one “A14”6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-ylmethyl)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A15”3-{1-[3-(5-methylpyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile “A16”N′-(2-[3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yl)-N,N-dimethylformamidine “A17”2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one “A18”6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A19”6-(3,5-difluorophenyl)-2-[3-(5-piperazin-1-ylpyrimidin-2-yl)-benzyl]-2H-pyridazin-3-one “A20”2-{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one “A21”6-(3,5-difluorophenyl)-2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-2H-pyridazin-3-one “A22”6-(3,5-difluorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A23”6-(3,5-difluorophenyl)-2-{3-[5-(1-methylpiperidin-4-yloxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A25” 2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one “A26”6-(3,5-difluorophenyl)-2-{3-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A29” ethyl2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carboxylate “A30” ethyl2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}pyrimidine-5-carboxylate

“A31” 2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidine-5-carboxylic acid “A32”2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidine-5-carboxylic acid “A33”N-(2-dimethylaminoethyl)-2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carboxamide “A34”

“A35”

“A36”

“A37”

“A38”

“A39”

“A40”

“A41”

“A42”

“A43”

“A44”

“A44a”

“A45”

“A46”

“A47”

“A48”

“A49”

“A50”

“A51” N-[2-(1H-imidazol-4-yl)ethyl]-2-{3-[6-oxo-3-(3,4,5-trifluoro-phenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5- carboxamide “A52”

“A53”

“A54” 2-[3-(5-chloropyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one “A55”4-{1-[3-(5-methylpyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}-N-(3-piperidin-1-ylpropyl)benzamide “A56”6-(3,5-difluorophenyl)-2-{3-[5-(3-pyrrolidin-1-ylpropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A57”6-(3,5-difluorophenyl)-2-(3-{5-[2-(4-methylpiperazin-1-yl)-ethoxy]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one “A58”6-(3,5-difluorophenyl)-2-[3-(5-dimethylaminomethylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one “A59”6-(3,5-difluorophenyl)-2-{3-[4-(methylpiperidin-4-yl-amino)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A60” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one “A63”

“A64” 2-{3-[5-(2-dimethylaminoethoxy)pyrimidin-2-yl]benzyl}-6-(3,5-difluorophenyl)-2H-pyridazin-3-one “A65”2-{3-[5-(piperazin-1-yl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluoro-phenyl)-2H-pyridazin-3-one “A66”6-(3,5-difluorophenyl)-2-{3-[5-(1-methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A71”

“A72”

“A73”

“A74”

“A75” 4-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pynmidin-5-yl)morpholin-3-one

“A76” N′-(2-{3-[3-(3,4,5-trifluorophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}pyrimidin-5-yl)-N,N-dimethylformamidine “A77”2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidine-5-carbonitrile

“A78” 6-[4-(3-dimethylaminopropoxy)-3,5-difluorophenyl]-2-[3-(5-methylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one

“A79” 6-benzo-1,2,5-thiadiazol-5-yl-2-[3-(5-methylpyrimidin-2-yl)-benzyl]-2H-pyridazin-3-one

“A80” 6-(3,5-difluorophenyl)-2-[3-(6-oxo-1,6-dihydropyrimidin-2-yl)-benzyl]-2H-pyridazin-3-one “A81” 6-(3,5-difluorophenyl)-2-{3-[4-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A82”2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one “A83”2-(3-pyrimidin-5-ylbenzyl)-6-(3,4,5-trifluorophenyl)-2H- pyridazin-3-one“A84”

“A85” N-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yl)-2-dimethylaminoacetamide “A87”N-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yl)-4-dimethylaminobutyramide

“A88”

“A89”

“A90”

“A92”

“A93” 2-[3-(5-aminomethylpyrimidin-2-yl)benzyl]-6-(3,4,5-trifluoro-phenyl)-2H-pyridazin-3-one “A95”N-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yl)-3-dimethylaminopropionamide

“A96” 3-(4-methylpiperazin-1-yl)-N-(2-{3-[6-oxo-3-(3,4,5-trifluoro-phenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-ylmethyl)-propionamide

“A97” 2-(4-methylpiperazin-1-yl)-N-(2-{3-[6-oxo-3-(3,4,5-trifluoro-phenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl- methyl)acetamide

“A98” 2-methylamino-N-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-ylmethyl)acetamide

“A99” 3-dimethylamino-N-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-ylmethyl)propionamide

“A100” 2-[3-(5-methylpyrimidin-2-yl)benzyl]-6-(2H-pyrazol-3-yl)-2H-pyridazin-3-one “A101”6-(3,5-difluorophenyl)-2-[3-(5-hydroxymethylpyrimidin-2-yl)-benzyl]-2H-pyridazin-3-one “A102”6-(3,5-difluorophenyl)-2-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one “A103”

“A104”

“A105”

“A106”

“A107”

“A108”

“A109”

“A110”

“A111”

“A112”

“A113”

“A114”

“A115”

“A116”

“A117”

“A118”

“A119” 6-(3,5-difluorophenyl)-2-{3-[5-(8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A120”

“A121” 6-(3,5-difluorophenyl)-2-{3-[5-((S)-1-methylpyrrolidin-3-yloxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one,

“A122” 6-(3,5-difluorophenyl)-2-{3-[5-((R)-1-methylpyrrolidin-3-yloxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, “A123”

“A124”

“A125”

“A126”

“A127” 6-(3,5-difluorophenyl)-2-{3-[5-(2-pyrrolidin-1-ylethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A128”6-(3,5-difluorophenyl)-2-{3-[5-(3-morpholin-4-ylpropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A129”

“A130” 6-(3,5-difluorophenyl)-2-{3-[5-(2-morpholin-4-ylethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, hydrochloride “A131”

“A132” 6-(3,5-difluorophenyl)-2-{3-[5-(4-methylaminobutoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A133”6-(3,5-difluorophenyl)-2-{3-[5-(3-methylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A134”6-(3,5-difluorophenyl)-2-{3-[5-(pyrrolidin-3-ylmethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A135”6-(3,5-difluorophenyl)-2-{3-[5-(3-ethylaminopropoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A136”2-{3-[5-(2-aminoethoxy)pyrimidin-2-yl]benzyl}-6-(3,5-difluoro-phenyl)-2H-pyridazin-3-one “A137”6-(3,5-difluorophenyl)-2-{3-[5-(piperidin-3-yloxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one “A138”6-(3,5-difluorophenyl)-2-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A139”6-(3,5-difluorophenyl)-2-{3-[5-(pyrrolidin-3-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A140”6-(3,5-difluorophenyl)-2-{3-[5-((S)-pyrrolidin-3-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A141”6-(3,5-difluorophenyl)-2-{3-[5-((R)-pyrrolidin-3-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A142”2-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-pyridin-4-yl-2H-pyridazin-3-one

“A143” 4-(6-oxo-1-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile

“A144” 3-(6-oxo-1-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile “A145”6-(3,5-difluorophenyl)-2-{3-[5-(2-piperazin-1-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A146”6-(3,5-difluorophenyl)-2-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one “A147”3-(6-oxo-1-{3-[5-(2-piperazin-1-ylethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile “A148”6-(3-fluorophenyl)-2-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A149”2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one

“A150” 3-(6-oxo-1-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile

“A151” 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A152” 6-(3-methoxyphenyl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A153”6-(3-fluorophenyl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A154”6-(3,5-difluorophenyl)-2-{3-[5-(1H-pyrazol-4-yl)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one

“A155” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-methylaminoethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one,

“A156” 6-(3-chlorophenyl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A157”

“A158” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(3-methylaminopropyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A159” 3-[1-(3-{5-[1-(2-methylaminoethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile

“A160” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A161” 3-(6-oxo-1-{3-[5-(1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile

“A162” 3-[6-oxo-1-(3-{5-[1-(2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}benzyl)-1,6-dihydropyridazin-3-yl]benzonitrile

“A163” N-(4-dimethylaminobutyl)-2-[3-(6-oxo-3-pyridin-4-yl-6H-pyridazin-1-ylmethyl)phenyl]pyrimidine-5-carboxamide

“A164” N-(4-dimethylaminobutyl)-2-{3-[3-(4-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carboxamide

“A165”

“A166”

“A167”

“A168”

“A169” 6-(1-methyl-1H-pyrazol-4-yl)-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A170” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A171” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-dimethylaminoethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A172” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(3-dimethylaminopropyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one “A173”6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one “A174”3-[1-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile

“A175” 2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-6-pyridin-3-yl-2H-pyridazin-3-one

“A176” 6-(1-methyl-1H-pyrazol-4-yl)-2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A177” 2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-6-pyridin-4-yl-2H-pyridazin-3-one “A178”6-(4-methanesulfonylphenyl)-2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one “A179”6-pyridin-4-yl-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one “A180”4-[6-oxo-1-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}benzyl)-1,6-dihydropyridazin-3-yl]benzonitrile

“A181” 2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-6-pyridin-4-yl-2H-pyridazin-3-one “A182”

“A183” 6-(4-methanesulfonylphenyl)-2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one “A184”6-(5-methyloxazol-2-yl)-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A185”6-(3-fluorophenyl)-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one “A186”6-(1-propyl-1H-pyrazol-4-yl)-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A187” 2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-6-thiophen-3-yl-2H-pyridazin-3-one

“A188”

“A188a”

“A189” 3-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A190”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one

“A191” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(3-fluorophenyl)-2H-pyridazin-3-one “A192”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-thiazol-2-yl-2H-pyridazin-3-one “A193”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-phenyl-2H-pyridazin-3-one “A194”4-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A195”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-p-tolyl-2H-pyridazin-3-one “A196”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(2H-pyrazol-3-yl)-2H-pyridazin-3-one “A197”6-(3,4-difluorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A198”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(4-methanesulfonylphenyl)-2H-pyridazin-3-one “A199”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2H-pyridazin-3-one “A200”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-pyridin-4-yl-2H-pyridazin-3-one “A201”6-(3-bromophenyl)-2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A202”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one “A203”6-(3,5-dimethoxyphenyl)-2-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A204”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one “A205”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(4-methoxyphenyl)-2H-pyridazin-3-one “A206”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(3-trifluoromethylphenyl)-2H-pyridazin-3-one, “A207”6-(3-chlorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A208”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-pyridin-3-yl-2H-pyridazin-3-one “A209”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A210”6-(3-chloro-5-fluorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A211”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(4-fluoro-3-methoxyphenyl)-2H-pyridazin-3-one “A212”6-(4-chlorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A213”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(4-fluorophenyl)-2H-pyridazin-3-one “A214”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-thiophen-2-yl-2H-pyridazin-3-one “A215”N-[4-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)phenyl]acetamide

“A216” 6-(3,4-dimethoxyphenyl)-2-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A217”6-benzo-1,2,5-thiadiazol-5-yl-2-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A218” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-turan-3-yl-2H-pyridazin-3-one “A219”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(5-methyl-1,2,4-oxadiazol-3-yl)-2H-pyridazin-3-one “A220”4-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A221”3-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A222”3-(1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A223”2-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-pyridin-4-yl-2H-pyridazin-3-one “A224”6-(4-methanesulfonylphenyl)-2-{3-[5-(1-methylpiperidin-4-yloxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A225” methyl5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2-carboxylate

“A226” 2-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A227”2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2H-pyridazin-3-one

“A228” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-piperazin-1-yl-2H-pyridazin-3-one

“A229” 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-ylethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A230”2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A231”2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A235”6-(3-fluorophenyl)-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A237”2-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A238”2-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A239”2-[3-(5-methoxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A240”2-{3-[5-(3-methoxypropoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A241”2-{3-[5-(2-methoxyethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A242”2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-6-(1-propyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A243”2-(3-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyrimidin-2-yl}-benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A244”2-(3-{5-[2-(4-methyl-3-oxopiperazin-1-yl)ethoxy]pyrimidin-2-yl}-benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one

“A245” 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(3-morpholin-4-ylpropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A246”6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-ylpropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A247” 2-{3-[5-(1-methyl-2-morpholin-4-ylethoxy)pyrimidin-2-yl]-benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one

“A248” 2-{3-[5-(2-dimethylaminoethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A249”2-{3-[5-(2-methyl-3-morpholin-4-ylpropoxy)pyrimidin-2-yl]-benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one

“A250” 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-pyrrolidin-1-ylethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A251”2-[3-(5-ethoxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A252”6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-yl-2-oxo-ethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A253” 6-(3-chlorophenyl)-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A254”

“A255”

“A256”

“A257” 3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A260”3-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzamide “A261”

“A262” 3-{1-[3-(5-bromopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile “A263”3-{1-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile “A264”3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile “A265” tert-butyl4-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxymethyl)piperidine-1- carboxylate “A266”6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(piperidin-4-yloxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A267”6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(piperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A268”3-(1-{3-[5-(3-methylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile

“A269” 3-[1-(3-{5-[2-(4-methyl-3-oxopiperazin-1-yl)ethoxy]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile

“A270” 3-[1-(3-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyrimidin-2-yl}-benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile “A271”3-(1-{3-[5-(2-methoxyethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A272”3-(1-{3-[5-(3-methoxypropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A273”6-(3-fluorophenyl)-2-{3-[5-(1-methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A274”2-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-(1-propyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A275”6-(3-chlorophenyl)-2-{3-[5-(1-methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “A276”

“A276a”

“A277” 5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2-carboxylic acid “A278”5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2-carboxamide “A279”N-methyl-5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2- carboxamide “A283”methyl (E)-3-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)acrylate “A284”2-{3-[5-((E)-3-aminopropenyl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one “A285”2-{3-[5-(3-aminopropyl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluoro-phenyl)-2H-pyridazin-3-one “A286”2-{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A287”3-(1-{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A288”3-{6-oxo-1-[3-(5-piperazin-1-ylpyrimidin-2-yl)benzyl]-1,6-dihydropyridazin-3-yl}benzonitrile “A289”6-(4-methanesulfonylphenyl)-2-[3-(5-piperazin-1-ylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one “A290”4-{1-[3-(5-aminopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile “A291”3-{1-[3-(5-aminopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile “A292”6-(1-methyl-1H-pyrazol-4-yl)-2-[3-(5-piperazin-1-ylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one “A293”2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A294”2-{3-[5-(2-hydroxyethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A295”3-(1-{3-[5-(3-hydroxypropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A296”3-(1-{3-[5-(2-hydroxyethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A297”2-{3-[5-(3-hydroxypropoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A298”3-[1-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}-ethyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile “A299”6-(3,5-difluorophenyl)-2-(1-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]phenyl}ethyl)-2H-pyridazin-3-one “A300”6-(3,5-difluorophenyl)-2-((R)-1-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]phenyl}ethyl)-2H-pyridazin-3-one “A301”6-(3,5-difluorophenyl)-2-((S)-1-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]phenyl}ethyl)-2H-pyridazin-3-one “A302”3-(1-{3-[5-(1-methyl-1-oxypiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A303”3-(1-{3-[5-(1-formylpiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A304”

“A305”

“A306”

“A307”

“A308”

“A309”

“A310”

“A311”

“A312”

“A313”

“A314”

or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomerthereof.
 21. A compound, which is one of the following compounds No.Name and/or structure “A23”6-(3,5-difluorophenyl)-2-{3-[5-(1-methylpiperidin-4-yloxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A30” ethyl 2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}pyrimidine-5-carboxylate

“A34”

“A35”

“A36”

“A37”

“A38”

“A39”

“A40”

“A41”

“A42”

“A43”

“A44”

“A44a”

“A45”

“A46”

“A47”

“A48”

“A49”

“A50”

“A52”

“A53”

“A59” 6-(3,5-difluorophenyl)-2-{3-[4-(methylpiperidin-4-yl-amino)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A63”

“A71”

“A72”

“A73”

“A74”

“A75” 4-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yl)morpholin-3-one

“A77” 2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidine-5-carbonitrile

“A78” 6-[4-(3-dimethylaminopropoxy)-3,5-difluorophenyl]-2-[3-(5-methylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one

“A79” 6-benzo-1,2,5-thiadiazol-5-yl-2-[3-(5-methylpyrimidin-2-yl)-benzyl]-2H-pyridazin-3-one

“A84”

“A87” N-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yl)-4-dimethylaminobutyramide

“A88”

“A89”

“A90”

“A92”

“A95” N-(2-{3-[3-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yl)-3-dimethylaminopropionamide

“A96” 3-(4-methylpiperazin-1-yl)-N-(2-{3-[6-oxo-3-(3,4,5-trifluoro-phenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-ylmethyl)-propionamide

“A97” 2-(4-methylpiperazin-1-yl)-N-(2-{3-[6-oxo-3-(3,4,5-trifluoro-phenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl- methyl)acetamide

“A98” 2-methylamino-N-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-ylmethyl)acetamide

“A99” 3-dimethylamino-N-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-ylmethyl)propionamide

“A103”

“A104”

“A105”

“A106”

“A107”

“A108”

“A109”

“A110”

“A111”

“A112”

“A113”

“A114”

“A115”

“A116”

“A117”

“A118”

“A119” 6-(3,5-difluorophenyl)-2-{3-[5-(8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A120”

“A121” 6-(3,5-difluorophenyl)-2-{3-[5-((S)-1-methylpyrrolidin-3-yloxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one,

“A123”

“A124”

“A125”

“A126”

“A129”

“A131”

“A142” 2-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-pyridin-4-yl-2H-pyridazin-3-one

“A143” 4-(6-oxo-1-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile

“A149” 2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one

“A150” 3-(6-oxo-1-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl]-1,6-dihydropyridazin-3-yl)benzonitrile

“A151” 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A154” 6-(3,5-difluorophenyl)-2-{3-[5-(1H-pyrazol-4-yl)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one

“A155” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-methylaminoethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one,

“A156” 6-(3-chlorophenyl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A157”

“A158” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(3-methylaminopropyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A159” 3-[1-(3-{5-[1-(2-methylaminoethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile

“A160” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A161” 3-(6-oxo-1-{3-[5-(1H-pyrazol-4-yl)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile

“A162” 3-[6-oxo-1-(3-{5-[1-(2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}benzyl)-1,6-dihydropyridazin-3-yl]benzonitrile

“A163” N-(4-dimethylaminobutyl)-2-[3-(6-oxo-3-pyridin-4-yl-6H-pyridazin-1-ylmethyl)phenyl]pyrimidine-5-carboxamide

“A164” N-(4-dimethylaminobutyl)-2-{3-[3-(4-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carboxamide

“A165”

“A166”

“A167”

“A168”

“A169” 6-(1-methyl-1H-pyrazol-4-yl)-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A170” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A171” 6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-dimethylaminoethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A174” 3-[1-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile

“A175” 2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-6-pyridin-3-yl-2H-pyridazin-3-one

“A176” 6-(1-methyl-1H-pyrazol-4-yl)-2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl]benzyl)-2H-pyridazin-3-one

“A180” 4-[6-oxo-1-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl]benzyl)-1,6-dihydropyridazin-3-yl]benzonitrile

“A182”

“A184” 6-(5-methyloxazol-2-yl)-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A186”6-(1-propyl-1H-pyrazol-4-yl)-2-(3-{5-[1-(2-[pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one

“A187” 2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}benzyl)-6-thiophen-3-yl-2H-pyridazin-3-one

“A188”

“A188a”

“A190” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one

“A215” N-[4-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)phenyl]acetamide

“A217” 6-benzo-1,2,5-thiadiazol-5-yl-2-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A225” methyl 5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2-carboxylate

“A227” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2H-pyridazin-3-one

“A228” 2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-piperazin-1-yl-2H-pyridazin-3-one

“A244” 2-(3-{5-[2-(4-methyl-3-oxopiperazin-1-yl)ethoxy]pyrimidin-2-y1}-benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one

“A246” 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-ylpropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A247” 2-{3-[5-(1-methyl-2-morpholin-4-ylethoxy)pyrimidin-2-yl]-benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one

“A249” 2-{3-[5-(2-methyl-3-morpholin-4-ylpropoxy)pyrimidin-2-yl]-benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one

“A252” 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-yl-2-oxo-ethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one

“A254”

“A255”

“A256”

“A261”

“A268” 3-(1-{3-[5-(3-methylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile

“A269” 3-[1-(3-{5-[2-(4-methyl-3-oxopiperazin-1-yl)ethoxy]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile

“A276”

“A276a”

“A304”

“A305”

“A306”

“A307”

“A308”

“A309”

“A310”

“A311”

“A312”

“A313”

“A314”

or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomerthereof.
 22. A compound according to claim 1, which is3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrileor a pharmaceutically acceptable solvate, salt, tautomer or stereoisomerthereof.
 23. A compound according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 24. A compound according to claim 20, or apharmaceutically acceptable salt thereof.
 25. A compound according toclaim 21, or a pharmaceutically acceptable salt thereof.
 26. A compoundaccording to claim 22, which is3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile,or a pharmaceutically acceptable salt thereof.
 27. A compound accordingto claim 22, which is3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile.28. A compound according to claim 1, in which R¹ denotes Ar or Het, R²denotes pyrimidinyl, which is monosubstituted by Hal, A,[C(R³)₂]_(n)OR³, N═CR³N(R³)₂, CN, COOR³, [C(R³)₂]_(n)N(R³)₂,[C(R³)₂]_(n)Het, O[C(R³)₂]_(p)OR³, O[C(R³)₂]_(n)N(R³)₂,O[C(R³)₂]_(n)C≡C[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)N⁺O⁻(R³)₂,O[C(R³)₂]_(n)Het, NR³[C(R³)₂]_(n)N(R³)₂, NR³[C(R³)₂]_(n)Het,[C(R³)₂]_(n)NHCO[C(R³)₂]_(n−)N(R³)₂, [C(R³)₂]_(n)NHCO[C(R³)₂]_(n)Het,CONR³[C(R³)₂]_(n)N(R³)₂, CONR³[C(R³)₂]_(n)NR³COOA, CONR³[C(R³)₂]_(n)OR³,CONR³[C(R³)₂]_(n)Het, COHet, CH═CH—COOR³, CH═CH—N(R³)₂ and/or ═O, R³denotes H, methyl, ethyl or propyl, R⁴, R^(4′) denote H, Ar denotesphenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-,di- or trisubstituted by A, Hal, CN, S(O)_(m)A, NR³COA, CON(R³)₂,O[C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)OR³, CONR³[C(R³)₂]_(n)N(R³)₂ and/orCONR³[C(R³)₂]_(n)Het, Het denotes piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl,azabicyclo[2.2.2]octyl, imidazolidinyl, azepanyl orbenzo-2,1,3-thiadiazolyl, each of which is unsubstituted or mono-, di-,tri-, tetra- or penta- substituted by A, CHO, COOR³, CON(R³)₂,[C(R³)₂]_(n)Het^(l), [C(R³)₂]_(n)OR³, [C(R³)₂]_(n)N(R³)₂,O[C(R³)₂]_(n)Het¹ and/or ═O, and where a ring nitrogen is optionallyoxidized, Het¹ denotes pyrrolidine, piperidine, piperazine ormorpholine, each of which is unsubstituted or mono- or disubstituted byA and/or ═O, A denotes unbranched or branched alkyl having 1-8 C atoms,in which 1-7 H atoms are optionally replaced by F, Hal denotes F, Cl, Bror I, m denotes 0, 1 or 2, n denotes 0, 1, 2, 3 or 4, and p denotes 1,2, 3 or 4, or a pharmaceutically acceptable solvate, salt, tautomer orstereoisomer thereof.
 29. A compound according to claim 28, or apharmaceutically acceptable salt thereof.